U.S. patent number 4,107,315 [Application Number 05/818,724] was granted by the patent office on 1978-08-15 for 5-(pyridinyl)-2(1h)-pyridinones.
This patent grant is currently assigned to Sterling Drug Inc.. Invention is credited to George Y. Lesher, Chester J. Opalka, Jr..
United States Patent |
4,107,315 |
Lesher , et al. |
August 15, 1978 |
**Please see images for:
( Certificate of Correction ) ** |
5-(Pyridinyl)-2(1H)-pyridinones
Abstract
Compounds useful as cardiotonic agents are
1-R-3-Q-5-PY-2(1H)-pyridinones (I) where R is hydrogen, lower-alkyl
or lower-hydroxyalkyl, Q is amino (preferred), lower-alkylamino,
di-(lower-alkyl)amino or NHAc, Ac is lower-alkanoyl or
lower-carbalkoxy, and PY is 4- or 3- or 2-pyridinyl or 4- or 3- or
2-pyridinyl having one or two lower-alkyl substituents. The
corresponding compounds where Q is nitro, carbamyl, cyano, halo or
hydrogen are useful as intermediates and those where Q is hydrogen
or cyano also are useful as cardiotonic agents. Said compounds are
prepared: by reacting .alpha.-PY-.beta.-(R.sub.1 R.sub.2 N)acrolein
(II) with malonamide to produce 1,2-dihydro-2-oxo-5-PY-nicotinamide
(Ia) and reacting Ia with a reagent capable of converting carbamyl
to amino to produce 3-amino-5-PY-2(1H)-pyridinone (Ib); by reacting
II or .alpha.-PY-malonaldehyde (II') with .alpha.-cyanoacetamide to
produce 1,2-dihydro-2-oxo-5-PY-nicotinonitrile (III) and partially
hydrolyzing III to produce Ia; and, by heating
1,2-dihydro-2-oxo-5-PY-nicotinic acid (IV) with a mixture of
concentrated sulfuric acid and concentrated nitric acid to produce
3-nitro-5-PY-2(1H)-pyridinone (Ic) and then either reducing Ic to
produce Ib or first reacting Ic with an alkylating agent to produce
1-R'-3-nitro-5-PY-2(1H)-pyridinone (Id) and reducing Id to produce
1-R'-3-amino-5-PY-2(1H)-pyridinone (Ib) where R' is lower-alkyl or
lower-hydroxyalkyl. Other derivatives of I where Q is amino are
shown.
Inventors: |
Lesher; George Y. (Schodack,
NY), Opalka, Jr.; Chester J. (Schodack, NY) |
Assignee: |
Sterling Drug Inc. (New York,
NY)
|
Family
ID: |
27089047 |
Appl.
No.: |
05/818,724 |
Filed: |
July 25, 1977 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
|
707235 |
Jul 21, 1976 |
4072746 |
|
|
|
621763 |
Oct 14, 1975 |
4004012 |
|
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|
Current U.S.
Class: |
514/334; 546/258;
546/257 |
Current CPC
Class: |
C07D
213/73 (20130101); C07D 213/53 (20130101); C07D
213/80 (20130101); C07D 213/74 (20130101); C07D
213/85 (20130101); C07D 213/75 (20130101); C07D
213/64 (20130101); C07D 213/48 (20130101); C07D
213/82 (20130101); C07D 213/38 (20130101) |
Current International
Class: |
C07D
213/48 (20060101); C07D 213/00 (20060101); C07D
213/38 (20060101); C07D 213/75 (20060101); C07D
213/53 (20060101); C07D 213/80 (20060101); C07D
213/85 (20060101); C07D 213/64 (20060101); C07D
213/74 (20060101); C07D 213/73 (20060101); C07D
213/82 (20060101); A61K 031/44 (); C07D
213/22 () |
Field of
Search: |
;260/295AM,295.5A,295L
;424/263,266 |
Other References
deVilliers et al., Chem. Abst. vol. 52, 1958, paragraph
1161(e)..
|
Primary Examiner: Trousof; Natalie
Assistant Examiner: Owens; Cary
Attorney, Agent or Firm: Bair; Robert K. Wyatt; B.
Woodrow
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation-in-part of copending application
Ser. No. 707,235, filed July 21, 1976 and now U.S. Pat. No.
4,072,746 issued Feb. 7, 1978, in turn, a continuation-in-part of
its copending application Ser. No. 621,763, filed Oct. 14, 1975,
now U.S. Pat. No. 4,004,012, issued Jan. 18, 1977.
Claims
We claim:
1. A 1-R-3-Q-5-PY-2(1H)-pyridinone having the formula: ##STR4##
where PY is 4- or 3- or 2-pyridinyl or 4- or 3- or 2-pyridinyl
having one or two lower-alkyl substituents, R is hydrogen,
lower-alkyl or lower hydroxy alkyl and Q is hydrogen or halo or a
pharmaceutically-acceptable acid-addition salt thereof.
2. A compound according to claim 1 where R and Q are each
hydrogen.
3. A compound according to claim 1 where Q is halo and R is
hydrogen.
4. 5-(4-Pyridinyl)-2(1H)-pyridinone according to claim 2.
5. 3-Chloro-5-(4-pyridinyl)-2(1H)-pyridinone according to claim
3.
6. 3-Bromo-5-(4-pyridinyl)-2(1H)-pyridinone according to claim
3.
7. A cardiotonic composition for increasing cardiac contractility,
said composition comprising a pharmaceutically-acceptable inert
carrier and, as the active component thereof, an effective amount
of a cardiotonic 1-R-3-Q-5-PY-2(1H)-pyridinone having the formula
##STR5## where PY is 4- or 3- or 2-pyridinyl or 4- or 3- or
2-pyridinyl having one or two lower-alkyl substituents, R is
hydrogen, lower-alkyl or lower-hydroxyalkyl and Q is hydrogen, or
pharmaceutically-acceptable acid-addition salt thereof.
8. A composition according to claim 7 where the active component is
5-(4-pyridinyl)-2(1H)-pyridinone.
9. The method for increasing cardiac contractility in a patient
requiring such treatment which comprises administering orally or
parenterally in a solid or liquid dosage form to such patient an
effective amount of a cardiotonic 1-R-3-Q-5-PY-2(1H)-pyridone
having the formula ##STR6## where PY is 4- or 3- or 2-pyridinyl or
4- or 3- or 2-pyridinyl having one or two lower-alkyl substituents,
R is hydrogen, lower-alkyl or lower-hydroxyalkyl and Q is hydrogen,
or pharmaceutically-acceptable acid-addition salt thereof.
10. The method according to claim 9 where the
1-R-3-Q-5-PY-2(1H)-pyridinone is
5-(4-pyridinyl)-2(1H)-pyridinone.
11. The process of preparing the compound of claim 1 where Q is
halo and R is hydrogen which comprises reacting
5-PY-2(1H)-pyridinone with halogen to produce
3-halo-5-PY-2(1H)-pyridinone where PY is defined as in claim 1.
12. The process for preparing the compounds of claim 1 where Q is
hydrogen which comprises reacting the corresponding compound where
Q is carboxy or cyano with aqueous mineral acid.
13. The process according to claim 12 which comprises reacting
1,2-dihydro-2-oxo-5-(4-pyridinyl)-nicotinonitrile or
1,2-dihydro-2-oxo-5-(4-pyridinyl)-nicotinic acid with aqueous
sulfuric acid to produce 5-(4-pyridinyl)-2(1H)-pyridinone.
14. The process for preparing the compound of claim 1 where Q is
halo which comprises the steps of heating
1,2-dihydro-2-oxo-5-PY-nicotinonitrile or
1,2-dihydro-2-oxo-5-PY-nicotinic acid with an aqueous mineral acid
to produce 5-PY-2(1H)-pyridinone and reacting 5-PY-2(1H)-pyridinone
with halogen to produce the corresponding
3-halo-5-PY-2(1H)-pyridinone.
15. The process which comprises the steps of reacting
1-R-5-PY-2(1H)-pyridinone with halogen to produce the corresponding
1-R-3-halo-5-PY-2(1H)-pyridinone according to claim 1 and reacting
said 3-halo compound with a lower-alkylamine or
di-(lower-alkyl)amine, to produce the corresponding respective
3-(lower-alkylamino) or 3-[di-(lower-alkyl)amino] compound, where
PY and R have the meanings given in claim 1.
Description
BACKGROUND OF THE INVENTION
(a) Field of the Invention
This invention relates to 3-amino-5-(pyridinyl)-2(1H)-pyridinones,
useful as cardiotonic agents, to their preparation and to
intermediates used therein.
(B) Description of the Prior Art
There is no teaching in the prior art of any cardiotonically active
compounds having any chemical structure comparable to or suggestive
of the instantly claimed compounds.
The Lesher and Gruett British Pat. No. 1,322,318, published July 4,
1973, discloses as intermediates 1,2-dihydro-2-oxo-6-(4- or
3-pyridinyl)-nicotinonitrile, 6-(4- or
3-pyridinyl)-2(1H)-pyridinone and 6-(4- or
3-pyridinyl)-2-pyridinamine.
The Brundage and Lesher U.S. Pat. No. 3,838,156, issued Sept. 24,
1974, discloses as intermediates 1,2-dihydro-2-oxo-6-Q'"-nicotinic
acids where Q'" is 4(or 3)-pyridinyl or 4(or 3)-pyridinyl having
one or two lower-alkyl substituents.
The Shionogi and Co. Japanese Pat. No. 20,295/67, published Oct.
11, 1967, shows 1-(x'-amino-2'-pyridinyl)-2-pyridinones as having
"analgesic and antiphlogistic activity". Specifically shown is
1-(5'-amino-2'-pyridinyl)-2-pyridinone.
SUMMARY OF THE INVENTION
In a composition aspect, the invention relates to
1-R-3-Q-5-PY-2(1H)-pyridinones where R is hydrogen, lower-alkyl or
lower-hydroxyalkyl, Q is carbamyl and halo, and PY is 4- or 3- or
2-pyridinyl or 4- or 3- or 2-pyridinyl having one or two
lower-alkyl substituents. The compounds where Q is carbamyl are
useful as intermediates in the preparation of the compounds where Q
is amino and those where Q is halo are useful as intermediates in
the preparation of the compounds where Q is lower-alkylamino and
di-(lower-alkyl)amino.
Another composition aspect of the invention relates to
1-R-3-Q-5-PY-2(1H)-pyridinones where Q is hydrogen and R and PY are
defined as above. These compounds not only are useful as
intermediates in preparing the corresponding compounds where Q is
amino, but also they surprisingly have been found to have useful
cardiotonic activity; and, further, they surprisingly have been
found to have useful bronchodilator activity.
The invention in a process aspect resides in the process of
producing 3-amino-5-PY-2(1H)-pyridinone (Ib) which comprises
reacting .alpha.-PY-.beta.-(R.sub.1 R.sub.2 N)acrolein (II) with
malonamide to produce 1,2-dihydro-2-oxo-5-PY-nicotinamide (Ia) and
reacting Ia with a reagent capable of converting carbamyl to amino
to produce Ib, where PY is defined as above, and R.sub.1 and
R.sub.2 are each lower-alkyl.
In another process aspect the invention comprises reacting either
.alpha.-PY-.beta.-(R.sub.1 R.sub.2 N)acrolein (II) or
.alpha.-PY-malonaldehyde (II') with .alpha.-cyanoacetamide to
produce 1,2-dihydro-2-oxo-5-PY-nicotinonitrile (III) and partially
hydrolyzing III to produce 1,2-dihydro-2-oxo-5-PY-nicotinamide
(Ia), where PY, R.sub.1 and R.sub.2 are each defined as above.
In another process aspect the invention comprises first heating
1,2-dihydro-2-oxo-5-PY-nicotinic acid (IV) with a mixture of
concentrated sulfuric acid and concentrated nitric acid to produce
3-nitro-5-PY-2(1H)-pyridinone (Ic) and then either reducing Ic to
produce 3-amino-5-PY-2(1H)-pyridinone (Ib) or first reacting Ic
with an alkylating agent of the formula R'-An to produce
1-R'-3-nitro-5-PY-2(1H)-pyridinone (Id) and reducing Id to produce
1-R'-3-amino-5-PY-2(1H)-pyridinone, where PY has the meaning given
above, R' is lower-alkyl or lower-hydroxyalkyl and An is an anion
of a strong inorganic acid or an organic sulfonic acid.
In another process aspect the invention comprises reacting
1-R-3-amino-5-PY-2(1H)-pyridinone with a lower-alkanoylating agent
or lower-carbalkoxylating agent to produce
1-R-3-Q'-5-PY-2(1H)-pyridinone (Ie), where PY and R have the
meanings given hereinabove and Q' is NHAc where Ac is
lower-alkanoyl or lower-carbalkoxy, respectively.
In another process aspect the invention comprises heating
1,2-dihydro-2-oxo-5-PY-nicotinonitrile (III) or
1,2-dihydro-2-oxo-5-PY-nicotinic acid (IV) with an aqueous mineral
acid, preferably aqueous sulfuric acid, to produce
5-PY-2(1H)-pyridinone (Ie) upon respective hydrolysis of III and
decarboxylation of IV, reacting Ie with halogen, preferably bromine
or chlorine, to produce the corresponding
3-halo-5-PY-2(1H)-pyridinone (If) and reacting If with a
lower-alkylamine or a di-(lower-alkyl)amine to produce the
corresponding 3-(lower-alkylamino)-5-PY-2(1H)-pyridinone (Ig-1) or
3-[di-(lower-alkyl)amino]-5-PY-2(1H)-pyridinone (Ig-2).
An alternative process aspect of the invention for preparing Ig-1
or Ig-2 comprises reacting 3-amino-5-PY-2(1H)-pyridinone with one
or two molar equivalents of a lower-alkylating agent. A preferred
embodiment of this alternative process comprises reacting
3-amino-5-PY-2(1H)-pyridinone with a methylating mixture of formic
acid and formaldehyde to produce
3-dimethylamino-5-PY-2(1H)-pyridinone where PY is defined as above
for I.
Another composition aspect of the invention relates to a
cardiotonic composition for increasing cardiac contractility, said
composition comprising a pharmaceutically-acceptable carrier and,
as the active component thereof, a cardiotonic
1-R-3-Q-5-PY-2(1H)-pyridinone where PY and R are defined as above
and Q is hydrogen.
In a method aspect, the invention relates to a method for
increasing cardiac contractility which comprises the administration
of a medicament comprising a pharmaceutically-acceptable carrier
and, as the active component thereof, an effective amount of a
cardiotonic 1-R-3-Q-5-PY-2(1H)-pyridinone where PY and R are
defined as above and Q is hydrogen.
Another composition aspect of the invention relates to
di-(lower-alkyl)
N-[1,2-dihydro-2-oxo-5-PY-3-pyridinyl]-aminomethylenemalonate where
PY is defined as above. These compounds also have been found to
have useful cardiotonic activity.
Another composition aspect of the invention relates to a
cardiotonic composition for increasing cardiac contractility, said
composition comprising a pharmaceutically-acceptable carrier and,
as the active component thereof, a cardiotonic di-(lower-alkyl)
N-[1,2-dihydro-2-oxo-5-PY-3-pyridinyl)aminomethylenemalonate, where
PY is defined as above.
In another method aspect, the invention relates to a method for
increasing cardiac contractility which comprises the administration
of a medicament comprising a pharmaceutically-acceptable carrier
and, as the active component thereof, an effective amount of a
cardiotonic di-(lower-alkyl)
N-[1,2-dihydro-2-oxo-5-PY-3-pyridinyl]aminomethylenemalonate where
PY is defined as above.
DETAILED DESCRIPTION INCLUSIVE OF PREFERRED EMBODIMENTS
In a composition aspect the invention resides in the compounds
having formula I ##STR1## where PY is 4- or 3- or 2-pyridinyl or 4-
or 3- or 2-pyridinyl having one or two lower-alkyl substituents, R
is hydrogen, lower-alkyl or lower-hydroxyalkyl, and Q is carbamyl
or halo, or pharmaceutically-acceptable acid-addition salt thereof.
The compounds of formula I where Q is amino, lower-alkylamino,
di-(lower-alkyl)amino, or NHAc are useful as cardiotonic agents, as
determined by standard pharmacological evaluation procedures. The
compounds of formula I where Q is carbamyl are useful as
intermediates for preparing the compounds where Q is amino and
those where Q is halo are useful as intermediates in the
preparation of the compounds where Q is lower-alkylamino and
di-(lower-alkyl)amino. Preferred embodiments are those of formula I
where Q is carbamyl, R is hydrogen and PY is 4-pyridinyl or
3-pyridinyl. A particularly preferred embodiment is
3-carbamyl-5-(4-pyridinyl)-2(1H)-pyridinone, that is,
1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinamide.
Other composition aspects resides in the compounds having formula I
where Q is hydrogen, or pharmaceutically-acceptable acid-addition
salt thereof. These compounds not only are useful as intermediates
for preparing the compounds of formula I where Q is amino, but also
are useful as cardiotonic agents and, also, are useful as
bronchodilators as determined by standard pharmacological
procedures. Preferred embodiments are those where PY is 4-pyridinyl
or 3-pyridinyl.
In a process aspect the invention resides in the process of
producing 3-amino-5-PY-2(1H)-pyridinone (Ib) which comprises
reacting .alpha.-PY-.beta.-(R.sub.1 R.sub.2 N)acrolein (II) with
malonamide to produce 1,2-dihydro-2-oxo-5-PY-nicotinamide (Ia) and
reacting 1,2-dihydro-2-oxo-5-PY-nicotinamide (Ia) with a reagent
capable of converting carbamyl to amino to produce
3-amino-5-PY-2(1H)-pyridinone (Ib), where PY is defined as in I
above, and R.sub.1 and R.sub.2 are each lower-alkyl, preferably
methyl or ethyl. Other process aspects of the invention reside in
each of two said steps, that is, the preparation of Ia from II and
the conversion of Ia to Ib.
In another process aspect the invention resides in the process of
reacting either .alpha.-PY-.beta.-(R.sub.1 R.sub.2 N)acrolein (II)
or .alpha.-PY-malonaldehyde (II') with .alpha.-cyanoacetamide to
produce 1,2-dihydro-2-oxo-5-PY-nicotinonitrile (III) and partially
hydrolyzing 1,2-dihydro-2-oxo-5-PY-nicotinonitrile (III) to produce
1,2-dihydro-2-oxo-5-PY-nicotinamide (Ia), where PY is defined as in
I above, and R.sub.1 and R.sub.2 are each lower-alkyl, preferably
methyl or ethyl.
In another process aspect the invention resides in the process of
producing 3-amino-1-R-5-PY-2(1H)-pyridinone (Ib) which comprises
first heating 1,2-dihydro-2-oxo-5-PY-nicotinic acid (IV) with a
mixture of concentrated sulfuric acid and concentrated nitric acid
to produce 3-nitro-5-PY-2(1H)-pyridinone (Ic) and then either
reducing 3-nitro-5-PY-2(1H)-pyridinone (Ic) to produce
3-amino-5-PY-2(1H)-pyridinone (Ib) or first reacting
3-nitro-5-PY-2(1H)-pyridinone (Ic) with an alkylating agent of the
formula R'-An to produce 1-R'-3-nitro-5-PY-2(1H)-pyridinone (Id)
and reducing 1-R'-3-nitro-5-PY-2(1H)-pyridinone (Id) to produce
1-R'-3-amino-5-PY-2(1H)-pyridinone (Ib), where R and PY have the
same meanings given hereinabove for formula I, and R' is
lower-alkyl or lower-hydroxyalkyl and An is an anion of a strong
inorganic acid or an organic sulfonic acid. Other process aspects
of the invention reside in the conversion of IV to Ic and in the
two-step conversion of IV to Ic to Id.
The above process aspects of the invention are illustrated by the
following flow sheet which also shows the conversion of
1,2-dihydro-2-oxo-5-PY-nicotinonitrile (III) to
1,2-dihydro-2-oxo-5-PY-nicotinic acid (IV) by hydrolysis with
aqueous sulfuric acid: ##STR2##
Alternatively, 1,2-dihydro-2-oxo-5-PY-nicotinonitrile (III) is
converted to 3-nitro-5-PY-2(1H)-pyridinone (Ic) via
5-PY-2(1H)-pyridinone (Ie) by first refluxing III with aqueous
sulfuric acid to produce 1,2-dihydro-2-oxo-5-PY-nicotinic acid (IV)
and then refluxing IV in solution (without isolation) to produce Ie
which is then heated with a mixture of concentrated sulfuric acid
and concentrated nitric acid to produce Ic.
In another process aspect the invention resides in the process of
producing 1-R-3-Q'-5-PY-2(1H)-pyridinone (Ie) which comprises
reacting 1-R-3-amino-5-PY-2(1H)-pyridinone (Ib) with a
lower-alkanoylating agent or lower-carbalkoxylating agent, where PY
and R have the meanings given hereinabove for the compounds of
formula I and Q' is NHAc where Ac is lower-alkanoyl or
lower-carbalkoxy, respectively.
In another process aspect the invention comprises the steps of
heating 1,2-dihydro-2-oxo-5-PY-nicotinonitrile (III) or
1,2-dihydro-2-oxo-5-PY-nicotinic acid (IV) with an aqueous mineral
acid, preferably aqueous sulfuric acid, to produce
5-PY-2(1H)-pyridinone (Ie) upon hydrolysis of III and
decarboxylation of IV, reacting Ie with halogen, preferably bromine
or chlorine, to produce the corresponding
3-halo-5-PY-2(1H)-pyridinone (If) and reacting If with a
lower-alkylamine (R.sub.1 NH.sub.2) or a di-(lower-alkyl)amine
(R.sub.1 R.sub.2 NH) to produce the corresponding
3-(lower-alkylamino)-5-PY-2(1H)-pyridinone (Ig where R.sub.1 is
lower-alkyl and R.sub.2 is hydrogen) or
3-[di-(lower-alkyl)amino]-5-PY-2(1H)-pyridinone (Ig where each of
R.sub.1 and R.sub.2 is lower-alkyl). This process aspect of the
invention also comprises said individual steps and combinations
thereof.
An alternative process aspect of the invention for preparing Ig
comprises reacting 3-amino-5-PY-2(1H)-pyridinone with one or two
molar equivalents of a lower-alkylating agent. A preferred
embodiment of this alternative process comprises reacting
3-amino-5-PY-2(1H)-pyridinone with a methylating mixture of formic
acid and formaldehyde to produce
3-dimethylamino-5-PY-2(1H)-pyridinone where PY is defined as above
for I.
The above additional process aspects of the invention are
illustrated by the following additional flow sheet which also shows
the conversion of 3-amino-5-PY-2(1H)-pyridinone (Ib) to
di-(lower-alkyl)
N-[1,2-dihydro-2-oxo-5-PY-3-pyridinyl]-aminomethylenemalonate (V):
##STR3## In the formulas of above flow sheet PY has the meaning
given hereinabove for formula I, R.sub.1 is lower-alkyl, R.sub.2 is
hydrogen or lower-alkyl, and R.sub.3 and R.sub.4 are each
lower-alkyl.
Another composition aspect of the invention resides in a
cardiotonic composition for increasing cardiac contractility, said
composition comprising a pharmaceutically-acceptable inert carrier
and, as the active component thereof, an effective amount of a
cardiotonic 1-R-3-Q-5-PY-2(1H)-pyridinone having the formula of
claim 1 where PY and R are each defined as in formula I and Q is
hydrogen, or pharmaceutically-acceptable acid-addition salt
thereof.
A method aspect of the invention resides in the method for
increasing cardiac contractility in a patient requiring such
treatment which comprises administering orally or parenterally in a
solid or liquid dosage form to such patient an effective amount of
a cardiotonic 1-R-3-Q-5-PY-2(1H)-pyridinone having the formula of
claim 1 where PY and R are each defined as in formula I and Q is
hydrogen, or pharmaceutically-acceptable acid-addition salt
thereof.
The compounds of formula I where Q is cyano and their use as
cardiotonic agents are disclosed and claimed in copending
application Ser. No. 621,763, filed Oct. 14, 1975, now U.S. Pat.
No. 4,004,012, issued Jan. 18, 1977.
The compounds of formula I where Q is amino, lower-alkylamino,
di-(lower-alkyl)amino or NHAc where Ac is lower-alkanoyl or
lower-carbalkoxy, as well as their use as cardiotonic agents, and
also the intermediate nitro compounds of formula I where Q is
nitro, are disclosed and claimed in copending application Ser. No.
707,235, filed July 21, 1976.
Another composition aspect of the invention relates to
di-(lower-alkyl)
N-[1,2-dihydro-2-oxo-5-PY-3-pyridinyl]aminomethylenemalonate (V)
where PY is defined as above, or pharmaceutically-acceptable
acid-addition salt thereof. These compounds also have been found to
have useful cardiotonic activity. A preferred embodiment of this
composition aspect is diethyl
N-[1,2-dihydro-2-oxo-5-4-(pyridinyl)-3-pyridinyl]aminomethylenemalonate.
Another composition aspect of the invention relates to a
cardiotonic composition for increasing cardiac contractility, said
composition comprising a pharmaceutically-acceptable inert carrier
and, as the active component thereof, an effective amount of a
cardiotonic di-(lower-alkyl)
N-[1,2-dihydro-2-oxo-5-PY-3-pyridinyl]aminomethylenemalonate (V)
where PY is defined as above, or pharmaceutically-acceptable
acid-addition salt thereof. A preferred embodiment of this
composition aspect is diethyl
N-[1,2-dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]aminomethylenemalonate.
In another method aspect, the invention relates to a method for
increasing cardiac contractility in a patient requiring such
treatment which comprises the administering orally or parenterally
in a solid or liquid dosage form to such a patient an effective
amount of a cardiotonic di-(lower-alkyl)
N-[1,2-dihydro-2-oxo-5-PY-3-pyridinyl]aminomethylenemalonate (V)
where PY is defined as above, or pharmaceutically-acceptable
acid-addition salt thereof.
The term "lower-alkyl" as used herein, e.g., as one of the meanings
for R or as a substituent for PY in formula I or as used in the Q
substituent when lower-alkylamino or di-(lower-alkyl)amino, means
alkyl radicals having from one to six carbon atoms which can be
arranged as straight or branched chains, illustrated by methyl,
ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl,
isobutyl, n-amyl, n-hexyl, and the like.
The term "lower-hydroxyalkyl", as used herein, e.g., as one of the
meanings for R in formula I, means hydroxyalkyl radicals having
from two to six carbon atoms and having its hydroxy groups and its
free valence bond (or connecting linkage) on different carbon
atoms, illustrated by 2-hydroxyethyl, 2-hydroxypropyl,
3-hydroxypropyl, 2-hydroxy-2-methylpropyl, 3-hydroxypropyl,
2-hydroxy-1,1-dimethylethyl, 4-hydroxybutyl, 5-hydroxyamyl,
6-hydroxyhexyl, and the like.
Illustrative of PY in formula I where PY is 4-, 3- or 2-pyridinyl
having one or two lower-alkyl substituents are the following [note
that "pyridinyl" as used herein is the same as "pyridyl", the
former now being the preferred term used in Chemical Abstracts]:
2-methyl-4-pyridinyl, 2,6-dimethyl-4-pyridinyl,
3-methyl-4-pyridinyl, 2-methyl-3-pyridinyl, 6-methyl-3-pyridinyl
(alternatively named 2-methyl-5-pyridinyl), 4-methyl-2-pyridinyl,
6-methyl-2-pyridinyl, 2,3-dimethyl-4-pyridinyl,
2,6-dimethyl-4-pyridinyl, 4,6-dimethyl-2-pyridinyl,
2-ethyl-4-pyridinyl, 2-isopropyl-4-pyridinyl,
2-n-butyl-4-pyridinyl, 2-n-hexyl-4-pyridinyl,
2,6-diethyl-4-pyridinyl, 2,6-diethyl-3-pyridinyl,
2,6-diisopropyl-4-pyridinyl, 2,6-di-n-hexyl-4-pyridinyl, and the
like.
The term "lower-alkanoyl", as used herein, e.g., as one of the
meanings for Ac in formula I, means alkanoyl radicals having from
one to six carbon atoms, including the straight- and branch-chained
radicals, illustrated by formyl, acetyl, propionyl (N-propanoyl),
butyryl (n-butanoyl), isobutyryl (2-methyl-n-propanoyl) and caproyl
(n-hexanoyl).
The term "lower-carbalkoxy", as used herein, e.g., as one of the
meanings for Ac in formula I, means carbalkoxy radicals where the
alkoxy portion can be straight- or branch-chained and has from one
to six carbon atoms, as illustrated by carbomethoxy, carbethoxy,
carbo-n-propoxy, carbisopropoxy, carbo-n-butoxy, carbo-tert.-butoxy
and carbo-n-hexoxy.
The compounds of formulas I and V are useful both in the free base
form and in the form of acid-addition salts; and, both forms are
within the purview of the invention. The acid-addition salts are
simply a more convenient form for use; and in practice, use of the
salt form inherently amounts to use of the base form. The acids
which can be used to prepare the acid-addition salts include
preferably those which produce, when combined with the free base,
pharmaceutically-acceptable salts, that is, salts whose anions are
relatively innocuous to the animal organism in pharmaceutical doses
of the salts, so that the beneficial cardiotonic properties
inherent in the free base are not vitiated by side effects
ascribable to the anions. In practicing the invention, it was found
convenient to form the sulfate, phosphate, methanesulfonate or
lactate. However, other appropriate pharmaceutically-acceptable
salts within the scope of the invention are those derived from
mineral acids such as hydrochloric acid and sulfamic acid; and
organic acids such as acetic acid, citric acid, tartaric acid,
ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,
cyclohexylsulfamic acid, quinic acid, and the like, giving the
hydrochloride, sulfamate, acetate, citrate, tartrate,
ethanesulfonate, benzenesulfonate, p-toluenesulfonate,
cyclohexylsulfamate and quinate, respectively.
The acid-addition salts of said basic compound are prepared either
by dissolving the free base in aqueous or aqueous-alcohol solution
or other suitable solvents containing the appropriate acid and
isolating the salt by evaporating the solution, or by reacting the
free base and acid in an organic solvent, in which case the salt
separates directly or can be obtained by concentration of the
solution.
Although pharmaceutically-acceptable salts of said basic compounds
are preferred, all acid-addition salts are within the scope of our
invention. All acid-addition salts are useful as sources of the
free base form even if the particular salt per se is desired only
as an intermediate product as for example when the salt is formed
only for purposes of purification or identification, or when it is
used as an intermediate in preparing a pharmaceutically-acceptable
salt by ion exchange procedures.
The molecular structures of the composition aspects (I) of the
invention were assigned on the basis of evidence provided by
infrared, ultraviolet, nuclear magnetic resonance and mass spectra,
by chromatographic mobilities, and, by the correspondence of
calculated and found values for the elementary analyses for
representative examples.
The manner of making and using the instant invention will now be
generally described so as to enable a person skilled in the art of
pharmaceutical chemistry to make and use the same, as follows:
The preparation of 1,2-dihydro-2-oxo-5-PY-nicotinamide (Ia) by
reacting .alpha.-PY-.beta.-(R.sub.1 R.sub.2 N)acrolein (II) with
malonamide is carried out preferably by mixing the reactants in a
suitable solvent in the presence of a basic condensing agent. The
reaction is conveniently run using a lower-alkanol as the solvent,
preferably methanol or ethanol, and an alkali lower-alkoxide,
preferably sodium methoxide or sodium ethoxide, respectively, as
the basic condensing agent. In practicing the invention, the
reaction was carried out in refluxing methanol using sodium
methoxide. Other basic condensing agents include sodium hydride,
lithium diethylamine, lithium diisopropylamide, and the like, in an
aprotic solvent, e.g., tetrahydrofuran, acetonitrile, ether,
benzene, dioxane, and the like.
The above-noted intermediate .alpha.-PY-.beta.-(R.sub.1 R.sub.2
N)acroleins (II) are generally known and are prepared by
conventional methods. For example, II is produced by reacting an
.alpha.-PY-acetic acid with the reaction product obtained by
reacting dimethylformamide with a phosphorus oxyhalide, preferably
the oxychloride or oxybromide. The reaction of dimethylformamide
with the phosphorus oxyhalide is run preferably below 10.degree. C.
and the resulting reaction product is heated with the
.alpha.-PY-acetic acid at about 50.degree. to 80.degree. C. to
produce II. The intermediate .alpha.-PY-acetic acids are generally
known compounds which are prepared by conventional methods; for
example, they are produced readily by heating the corresponding
acetylpyridine of the formula PY-COCH.sub.3 with sulfur and
morpholine to produce the corresponding PY-thioacetomorpholinamide
which on refluxing with 12N hydrochloric acid yields the
.alpha.-PY-acetic acid, e.g., .alpha.-(3-ethyl-4-pyridinyl)acetic
acid, is produced from 4-acetyl-3-ethylpyridine via
3-ethyl-4-pyridinylthioacetomorpholinamide [Jain et al., Indian
Journal of Chemistry 10, 455 (1972)]. The acetylpyridines, i.e.,
PY-COCH.sub.3, also are generally known compounds which are
prepared by conventional procedures, e.g., production from the
corresponding cyanopyridines, i.e., PY-CN, [Reilly Tar & Chem.
Corp. British Patent No. 920,303, published March 6, 1963; Case et
al., J. Am. Chem. Soc. 78, 5842 (1956)].
The conversion of 1,2-dihydro-2-oxo-5-PY-nicotinamide (Ia) to
3-amino-5-PY-2(1H)-pyridinone (Ib) is carried out by reacting Ia
with a reagent capable of converting carbamyl to amino. This
reaction is conveniently run by heating an aqueous mixture
containing an alkali metal hypohalite, preferably hypobromite or
hypochlorite, and Ia, and then acidifying the reaction mixture,
preferably with an aqueous mineral acid, e.g., hydrochloric acid.
The reaction can be carried out from about 25.degree. C. to
100.degree. C., preferably about 60.degree. C. to 100.degree.
C.
The reaction of .alpha.-PY-.beta.-(R.sub.1 R.sub.2 N)acrolein (II)
with .alpha.-cyanoacetamide to produce
1,2-dihydro-2-oxo-5-PY-nicotinonitrile (III) is carried out
preferably by mixing the reactants in a suitable solvent in the
presence of a basic condensing agent. The reaction is conveniently
run using a lower-alkanol as a solvent, preferably methanol or
ethanol, and an alkali lower-alkoxide, preferably sodium methoxide
or sodium ethoxide, respectively, as the basic condensing agent. In
practicing the invention, the reaction was carried out in refluxing
methanol using sodium methoxide. Other basic condensing agents
include sodium hydride, lithium diethylamide, lithium
diisopropylamide, and the like, in an aprotic solvent, e.g.,
tetrahydrofuran, acetonitrile, ether, benzene, dioxane, and the
like.
The reaction of .alpha.-PY-malonaldehyde (II') with
.alpha.-cyanoacetamide to produce
1,2-dihydro-2-oxo-5-PY-nicotinonitrile (III) is carried out by
heating the reactants in the presence of a catalytic condensing
agent, preferably morpholine or piperidine and/or its acetate. The
reaction is conveniently carried out by refluxing a benzene
solution containing the reactants in the presence of morpholine,
piperidine, morpholine acetate, piperidine acetate or mixtures
thereof, preferably with a water separator attached to the reaction
vessel to collect the water produced by the reaction.
The partial hydrolysis of 1,2-dihydro-2-oxo-5-PY-nicotinonitrile
(III) to produce 1,2-dihydro-2-oxo-5-PY-nicotinamide (Ia) is
carried out by heating III with concentrated sulfuric acid. While
the reaction is conveniently and preferably run by heating the
reactants on a steam bath, the temperature range for the reaction
can vary from about 25.degree. to 135.degree. C. Alternatively, the
conversion of III to Ia can be carried out by heating III at about
100.degree. to 175.degree. C. with polyphosphoric acid for about 1
to 5 hours.
The hydrolysis of 1,2-dihydro-2-oxo-5-PY-nicotinonitrile (III) to
produce 1,2-dihydro-2-oxo-5-PY-nicotinic acid (IV) is conveniently
run by heating III on a steam bath with an aqueous mineral acid,
preferably 50% sulfuric acid.
The conversion of 1,2-dihydro-2-oxo-5-PY-nicotinic acid (IV) to
3-nitro-5-PY-2(1H)-pyridinone (Ic) is carried out by heating IV
with a mixture of concentrated sulfuric acid and concentrated
nitric acid. The heating of the reactants is conducted at about
60.degree. to 100.degree. C., preferably at about 70.degree. to
90.degree. C. Although it might be presumed that the nicotinic acid
(IV) is first decarboxylated to produce the corresponding
3-unsubstituted-5-PY-2(1H)-pyridinone, which is then nitrated at
the 3-position, it is noted, as shown above, that heating the
corresponding nicotinonitrile (III) with concentrated sulfuric acid
alone results in partial hydrolysis yielding the corresponding
nicotinamide (Ia).
Alternatively, 1,2-dihydro-2-oxo-5-PY-nicotinonitrile (III) is
readily converted step-wise to 3-nitro-5-PY-2(1H)-pyridinone (Ic)
by first heating III with aqueous sulfuric acid for a longer period
(supra) than required to form 1,2-dihydro-2-oxo-5-PY-nicotinic acid
(IV) whereupon IV is first formed and then is decarboxylated on
continued heating to produce 1,2-dihydro-2-oxo-5-PY-pyridine which
is then nitrated under the same reaction conditions noted above for
converting IV to Ic, that is, by heating
1,2-dihydro-2-oxo-5-PY-pyridine with a mixture of concentrated
sulfuric acid and concentrated nitric acid to produce
3-nitro-5-PY-2(1H)-pyridinone (Ic).
The reaction of 3-nitro-5-PY-2(1H)-pyridinone (Ic) with a
lower-alkylating agent to produce
1-R'-3-nitro-5-PY-2(1H)-pyridinone (Id) is generally carried out by
reacting Ic with a lower-alkyl or a lower-hydroxyalkyl ester of a
strong inorganic acid or an organic sulfonic acid, said ester
having the formula R'-An, where An is an anion of a strong
inorganic acid or an organic sulfonic acid, e.g., chloride,
bromide, idodide, sulfate, methanesulfonate, benzenesulfonate, and
para-toluenesulfonate (or tosylate), and R' is lower-alkyl or
lower-hydroxyalkyl. This alkylation is preferably run using a
slight excess of the alkylating agent although equimolar quantities
give satisfactory results. The chloride, bromide, iodide or
tosylate is preferred because of the ready availability of the
requisite lower-alkyl halides or tosylates; and, the reaction is
carried out preferably in the presence of an acid-acceptor. The
acid-acceptor is a basic substance which preferably forms freely
water-soluble by-products easily separable from the product of the
reaction, including for example, sodium hydroxide, potassium
hydroxide, sodium carbonate, potassium carbonate, sodium alkoxides,
potassium alkoxides, sodium amide, and the like. The acid-acceptor
picks up the hydrogen halide or tosylate (or HAn) which is split
out during the course of the reaction. The reaction is preferably
carried out in the presence of a suitable solvent which is inert
under the reaction conditions, e.g., a solvent such as
lower-alkanol, acetone, dioxane, dimethylformamide, dimethyl
sulfoxide, hexamethyl phosphoramide, or a mixture of solvents,
e.g., a mixture of water and a lower-alkanol. The reaction is
generally carried out at a temperature between about room
temperature (about 20.degree.-25.degree. C.) and 150.degree. C.,
preferably heating on a steam bath in a stirred mixture of
dimethylformamide and anhydrous potassium carbonate.
The reduction of 3-nitro-5-PY-2(1H)-pyridinone or
1-R'-3-nitro-5-PY-2(1H)-pyridinone (Id) to produce
1-R-3-amino-5-PY-2(1H)-pyridinone (Ib) can be carried out either by
catalytic or chemical reductive means. In practicing the invention,
the hydrogenation of Ic or Id to produce Ib was conveniently run in
a suitable solvent, e.g., dimethylformamide, in the presence of a
hydrogenation catalyst, e.g., palladium-on-charcoal, at room
temperature (about 20.degree. to 25.degree. C.) until the uptake of
hydrogen ceased. Other suitable solvents include tetrahydrofuran,
dioxane, methanol, ethanol, water (containing a base, e.g., sodium
hydroxide, potassium hydroxide, triethylamine, etc.), and the like.
Other suitable hydrogenation catalysts include Raney nickel,
platinum oxide, and the like. Chemical reducing agents useful in
the reduction of Ic or Id to produce Ib include iron and acetic
acid, zinc and hydrochloric acid, and the like.
The acylation of 1-R-3-amino-5-PY-2(1H)-pyridinone (Ib) to produce
the corresponding 1-R-3-Q'NH-5-PY-2(1H)-pyridinone (Ie) is carried
out by reacting Ib with a lower-alkanoylating agent or a
lower-carbalkoxylating agent, e.g., a lower-alkanoyl halide,
preferably chloride, a lower-alkanoic anhydride, a lower-alkyl
haloformate, and the like, preferably in the presence of an
acid-acceptor, as illustrated hereinabove for the lower-alkylation
reaction. The lower-carbalkoxylation reaction can be carried out
step-wise by first reacting the
1-R-3-amino-5-PY-1-R-2(1H)-pyridinone (Ib) with
1,1'-carbonyldiimidazole in the presence of a suitable solvent,
e.g., dimethylformamide, to produce
N-(1-R-1,2-dihydro-2-oxo-5-PY-3-pyridinyl)-imidazole-1-carboxamide
which is then heated with a lower-alkanol to yield the
corresponding lower-alkyl
N-(1-R-1,2-dihydro-2-oxo-5-PY-3-pyridinyl)carbamate.
The reaction of 5-PY-2(1H)-pyridinone (Ie) with halogen to produce
3-halo-5-PY-2(1H)-pyridinone (If) is carried out preferably by
mixing the reactants in an appropriate solvent inert under the
reaction conditions, a preferred solvent being acetic acid. The
reaction is conveniently run at room temperature or by heating at
moderate temperatures up to about 100.degree. C. Preferred halogens
are bromine and chlorine. Any inert solvent can be used, e.g.,
dimethylformamide, chloroform, ethanol, and the like.
The reaction of 3-halo- 5-PY-2(1H)-pyridinone (If) with a
lower-alkylamine or a di-(lower-alkyl)amine to produce the
corresponding 3-(lower-alkylamino)-5-PY-2(1H)-pyridinone (Ig;
R.sub.1 is lower-alkyl and R.sub.2 is hydrogen) or
3-[di-(lower-alkyl)amino]-5-PY-2(1H)-pyridinone (Ig; R.sub.1 and
R.sub.2 are each lower-alkyl), respectively, is carried out by
heating the reactants in an autoclave at about
100.degree.-180.degree. C., preferably about
125.degree.-160.degree. C. and preferably using a suitable solvent,
e.g., water, dimethylformamide, dioxane, 1,2-dimethoxyethane, and
the like, or mixtures thereof.
A preferred method of preparing the
3-dimethylamino-5-PY-2(1H)-pyridinone is carried out by reacting
3-amino-5-PY-2(1H)-pyridinone (Ib) with a mixture of formaldehyde
and formic acid to effect dimethylation of the primary 3-amino
group. This reaction is conveniently carried out by refluxing the
3-amino-5-PY-2(1H)-pyridinone (Ib) with an excess each of
formaldehyde, preferably an aqueous solution thereof, and formic
acid, preferably more than a two-fold molar excess of each.
The following examples will further illustrate the invention
without, however, limiting it thereto.
A. 1,2-DIHYDRO-2-OXO-5-(PYRIDINYL)NICOTINONITRILES
A-1. 1,2-Dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile - A reaction
mixture containing 35 g. of
.alpha.-(4-pyridinyl)-.beta.-dimethylaminoacrolein, 21.6 g. of
sodium methoxide, 500 ml. of methanol and 17 g. of
.alpha.-cyanoacetamide was heated to reflux with stirring whereupon
an exothermic reaction ensued sufficient to cause the reaction
mixture to reflux without the use of external heat. The reaction
mixture was then refluxed with stirring for an additional thirty
minutes, with solid precipitating after about five minutes of
refluxing. The reaction mixture was cooled and the precipitate was
collected, washed with ethyl ether and dried. The solid produce was
recrystallized from methanol and dried in vacuo at 80.degree. C. to
yield 13 g. of 1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile as
its sodium salt, m.p. >300.degree. C. Subsequent concentrations
of the mother liquor yielded additional fractions of 10 g., 6.5 g.
and 3 g. of the product, thereby resulting in a total of 32.5 g. of
said sodium salt which is readily converted by treatment with
hydrochloric acid as in Example A-2 to the corresponding N-H
compound, that is,
1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile.
An alternative method of preparing
1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile is given as
follows: A mixture of containing 15 g. of
.alpha.-(4-pyridinyl)malonaldehyde, 9.3 g. of
.alpha.-cyanoacetamide, 11 g. of morpholine, 13 g. of acetic acid
and 1 liter of benzene was refluxed for about twenty-four hours
with a water separator connected to the reaction vessel, then
allowed to stand over the weekend. The solid which had separated
was collected, recrystallized from dimethylformamide and dried in
vacuo at 90.degree. C. for about 15 hours to yield 5 g. of
1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile, m.p.
>300.degree. C.
A-2. 1,2-Dihydro-2-oxo-5-(3-pyridinyl)nicotinonitrile - A mixture
containing 93 g. of
.alpha.-(3-pyridinyl)-.beta.-dimethylaminoacrolein, 54 g. of
.alpha.-cyanoacetamide, 65 g. of sodium methoxide and 900 ml. of
methanol was refluxed with stirring for two hours and then allowed
to stand at room temperature overnight. The resulting semi-solid
cake was cooled and the solid was collected, washed with isopropyl
alcohol and then ethyl ether and dried. The solid (sodium salt) was
dissolved in water, the aqueous solution neutralized with 6N
hydrochloric acid, and the acidic solution was cooled. The
separated solid was collected, washed successively with isopropyl
alcohol and ether and dried in vacuo at 80.degree. C. to yield 41
g. of 1,2-dihydro-2-oxo-5-(3-pyridinyl)nicotinonitrile, m.p.
>300.degree. C.
The above intermediate
.alpha.-(3-pyridinyl)-.beta.-dimethylaminoacrolein was prepared as
follows: to 740 ml. of dimethylformamide kept below 10.degree. C.
was added dropwise with stirring 294 g. of phosphorus oxychloride
and stirring was continued for another fifteen minutes then there
was added 88 g. of .alpha.-(3-pyridinyl)acetic acid and the
resulting reaction mixture was stirred at room temperature for 1
hour and then heated with stirring at about 70.degree. C. for 2
hours and then cooled. The reaction mixture was then evaporated in
vacuo to remove all of the volatile materials and the residue was
added slowly to 1.24 liters of saturated potassium carbonate
solution and 500 ml. of benzene with cooling. The mixture was
allowed to stand overnight and then extracted with four portions of
50/50 (v/v) of benzene/ethanol. The combined extracts were dried
over anhydrous potassium carbonate and evaporated in vacuo to
remove the solvent and thereby yield 136 g. of dark oily material
containing .alpha.-(3-pyridinyl)-.beta.-dimethylacrolein.
A-3. 1,2-Dihydro-2-oxo-5-(2-pyridinyl)nicotinonitrile - A mixture
containing 51 g. of
.alpha.-(2-pyridinyl)-.beta.-dimethylaminoacrolein, 24 g. of
.alpha.-cyanoacetamide, 31 g. of sodium methoxide and 500 ml. of
methanol was refluxed with stirring for four hours and then allowed
to stand at room temperature overnight. The mixture was filtered
and the filtrate evaporated in vacuo to remove the volatile
materials. The residue was diluted with water and the mixture
neutralized with 6N hydrochloric acid. The separated solid was
collected, washed successively with water, ethanol and ether and
then dried at 80.degree. C. in vacuo to yield 18 g. of
1,2-dihydro-2-oxo-5-(2-pyridinyl)nicotinonitrile.
The above intermediate
.alpha.-(2-pyridinyl)-.beta.-dimethylaminoacrolein was prepared
following the procedure described in Example A-2 using 50 g. of
.alpha.-(2-pyridinyl)acetic acid hydrochloride, 336 ml. of
dimethylformamide and 80 ml. of phosphorus oxychloride.
Following the procedure described in Example A-2 but using in place
of place of .alpha.-(3-pyridinyl)-.beta.-dimethylaminoacrolein a
molar equivalent quantity of the appropriate
.alpha.-PY-.beta.-dimethylaminoacrolein, the
1,2-dihydro-2-oxo-5-PY-nicotinonitrile of Examples A-4 thru A-7 are
obtained. The intermediate .alpha.-PY-.beta.-dimethylaminoacroleins
used in Examples A-4 thru A-7 are prepared by following the
procedure described in the second paragraph of Example A-2 to
produce .alpha.-(3-pyridinyl)-.beta.-dimethylaminoacrolein but
using in place of .alpha.-(3-pyridinyl)acetic acid a molar
equivalent quantity of the appropriate .alpha.-PY-acetic acid.
A-4. 1,2-Dihydro-2-oxo-5-(2-methyl-3-pyridinyl)nicotinonitrile
using .alpha.-(2-methyl-3-pyridinyl)-.beta.-dimethylaminoacrolein,
in turn prepared from .alpha.-(2-methyl-3-pyridinyl)acetic
acid.
A-5. 1,2-Dihydro-2-oxo-5-(5-methyl-3-pyridinyl)nicotinonitrile
using .alpha.-(5-methyl-3-pyridinyl)-.beta.-dimethylaminoacrolein,
in turn prepared from .alpha.-(5-methyl-3-pyridinyl)acetic
acid.
A-6. 1,2-Dihydro-2-oxo-5-(3-ethyl-4-pyridinyl)nicotinonitrile using
.alpha.-(3-ethyl-4-pyridinyl)-.beta.-dimethylaminoacrolein, in turn
prepared from .alpha.-(3-ethyl-4-pyridinyl)acetic acid.
A-7. 1,2-Dihydro-2-oxo-5-(4,6-dimethyl-2-pyridinyl)nicotinonitrile
using
.alpha.-(4,6-dimethyl-2-pyridinyl)-.beta.-dimethylaminoacrolein, in
turn prepared from .alpha.-(4,6-dimethyl-2-pyridinyl)acetic
acid.
B. 1,2-DIHYDRO-2-OXO-5-(PYRIDINYL)NICOTINIC ACIDS
B-1. 1,2-Dihydro-2-oxo-5-(4-pyridinyl)nicotinic acid - A mixture
containing 227 g. of
1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile and 2.6 liters of
50% aqueous sulfuric acid was refluxed for 5 hours and then allowed
to stand at room temperature overnight (about 15 hours). The
reaction mixture was then poured into 1 liter of water and the
mixture cooled. The precipitate was collected, washed successively
with water, ethanol and ether, and dried overnight in a vacuum oven
at 80.degree. C. to yield 206 g. of the crude product as a pink
solid. A 40 g. portion of the crude product was mixed with water
and the mixture neutralized by addition of potassium carbonate. The
solid was collected, washed successively with water, methanol, and
ether, and then recrystallized from dimethylformamide followed by
successive washing with methanol and ether, and then drying in
vacuo at 80.degree. C. to yield, as a white solid, 27 g. of
1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinic acid, m.p. >
300.degree. C.
B-2. 1,2-Dihydro-2-oxo-5-(3-pyridinyl)nicotinic acid - A mixture
containing 41 g. of
1,2-dihydro-2-oxo-5-(3-pyridinyl)nicotinonitrile and 410 ml. of 50%
aqueous sulfuric acid was refluxed for 2 hours and then poured into
1.5 kg. of a mixture of ice and water. The acidic mixture was
neutralized with 35% aqueous sodium hydroxide solution and the
mixture cooled. The separated solid was collected, washed with
water and dried in vacuo at 80.degree. C. to yield 47 g. of
1,2-dihydro-2-oxo-5-(3-pyridinyl)nicotinic acid which was used
directly without further purification in the next step described
below as Example C-2.
B-3. 1,2-Dihydro-2-oxo-5-(2-pyridinyl)nicotinic acid, 1.4 g., was
obtained following the procedure described in Example B2 using 18
g. of 1,2-dihydro-2-oxo-5-(2-pyridinyl)nicotinonitrile, 180 ml. of
50% aqueous sulfuric acid and a reflux period of 4 hours.
Following the procedure described in Example B-2 but using in place
of 1,2-dihydro-2-oxo-5-(3-pyridinyl)nicotinonitrile a molar
equivalent quantity of a 1,2-dihydro-2-oxo-5-PY-nicotinonitrile,
the corresponding 1,2-dihydro-2-oxo-5-PY-nicotinic acids of
Examples B-4 thru B-7 are obtained.
B-4. 1,2-Dihydro-2-oxo-5-(2-methyl-3-pyridinyl)nicotinic acid using
1,2-dihydro-2-oxo-5-(2-methyl-3-pyridinyl)nicotinonitrile.
B-5. 1,2-Dihydro-2-oxo-5-(5-methyl-3-pyridinyl)nicotinic acid using
1,2-dihydro-2-oxo-5-(5-methyl-3-pyridinyl)nicotinonitrile.
B-6. 1,2-Dihydro-2-oxo-5-(3-methyl-4-pyridinyl)nicotinic acid using
1,2-dihydro-2-oxo-5-(3-ethyl-4-pyridinyl)nicotinonitrile.
B-7. 1,2-Dihydro-2-oxo-5-(4,6-dimethyl-2-pyridinyl)-nicotinic acid
using
1,2-dihydro-2-oxo-5-(4,6-dimethyl-2-pyridinyl)-nicotinonitrile.
C. 3-NITRO-5-(PYRIDINYL)-2(1H)-PYRIDINONES
C-1. 3-Nitro-5-(4-pyridinyl)-2(1H)-pyridinone - To a stirred
solution kept at 5.degree.-10.degree. C. and containing 154 g. of
1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinic acid in 450 ml. of
concentrated sulfuric acid was added dropwise a solution containing
45 ml. of concentrated sulfuric acid and 160 ml. of 90% nitric
acid. The reaction mixture was heated cautiously at 80.degree. C.
for 3 hours and then poured into 3.3 liters of a mixture of ice and
water. The mixture was filtered and the precipitate washed with
water. The combined filtrates were added slowly to one liter of 10%
aqueous potassium carbonate solution with stirring. The solution
was neutralized by adding potassium carbonate and then made
alkaline by adding 5% aqueous sodium bicarbonate solution. The
precipitated product was collected, washed successively with a
small amount of cold water, isopropyl alcohol and ether, and then
dried in vacuo at 80.degree. C. to yield 89 g. of the product. A 30
g. portion of the product was recrystallized from dimethylformamide
to yield 20 g. of 3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone, m.p.
>300.degree. C.
Alternatively, 3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone is prepared
step-wise starting with
1,2-dihydro-2-oxo-5-(4-pyridinyl)-nicotinonitrile as follows: A
mixture containing 197 g. of
1,2-dihydro-2-oxo-5-(4-pyridinyl)-nicotinonitrile, 600 ml. of
concentrated sulfuric acid and 150 liters of water was refluxed for
24 hours, cooled and poured into 10 liters of a mixture of ice and
water. The mixture was neutralized with ammonium hydroxide and the
separated precipitate was collected, washed with a small amount of
cold water and dried in vacuo at 80.degree. C. to yield 148 g. of
5-(4-pyridinyl)-2(1H)-pyridinone, m.p. 258.degree.-260.degree. C.
An 80 g. portion of 5-(4-pyridinyl)-2(1H)-pyridinone was added to
288 ml. of concentrated sulfuric acid and the mixture heated to
70.degree. C. To this stirred solution kept at
70.degree.-80.degree. C. was added dropwise a mixture containing
102 ml. of 90% nitric acid and 29 ml. of concentrated sulfuric
acid. The reaction mixture was heated at about 80.degree. C for 3
hours after addition of the mixture of acids. The reaction mixture
was then cooled and poured into a mixture of ice and water with
stirring. The precipitate was collected and dried. It was then
slurried with water and neutralized with 10% aqueous potassium
bicarbonate solution. The precipitate was collected, washed with
water and dried in vacuo at 80.degree. C. to yield 56 g. of
3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone.
Following the procedure described in the immediately preceding
paragraph but starting with a molar equivalent quantity of the
appropriate 1,2-dihydro-2-oxo-5-PY-nicotinonitrile in place of
1,2-dihydro-2-oxo-5-(4-pyridinyl)-nicotinonitrile, there are
obtained first the following 5-PY-2(1H)-pyridinones:
5-(3-pyridinyl)-2(1H)-pyridinone; 5-(2-pyridinyl)-2(1H)-pyridinone;
5-(2-methyl-3-pyridinyl)-2(1H)-pyridinone;
5-(5-methyl-3-pyridinyl)-2(1H)-pyridinone;
5-(3-ethyl-4-pyridinyl)-2(1H)-pyridinone; and,
5-(4,6-dimethyl-2-pyridinyl)-2(1H)-pyridinone. In the subsequent
second step, that is, the treatment of the appropriate
5-PY-2(1H)-pyridinone with concentrated sulfuric acid and
concentrated nitric acid as above, there are obtained the
corresponding respective 3-nitro compounds.
C-2. 3-Nitro-5-(3-pyridinyl)-2(1H)-pyridinone, 14 g., m.p.
>300.degree. C., was prepared following the procedure described
in Example C-1 using 25 g. of
1,2-dihydro-2-oxo-5-(3-pyridinyl)nicotinic acid, 76.4 ml. of
concentrated sulfuric acid, 26.6 ml. of 90% nitric acid and 7.6 ml.
of concentrated sulfuric acid.
C-3. 3-Nitro-5-(2-pyridinyl)-2(1H)-pyridinone, 10 g., m.p.
>300.degree. C., was prepared following the procedure described
in Example C-1 using 14 g. of
1,2-dihydro-2-oxo-5-(2-pyridinyl)nicotinic acid, 44 ml. of
concentrated sulfuric acid, 15 ml. of 90% nitric acid and 4.4 ml.
of concentrated surfuric acid.
C-4. 1-Methyl-3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone - A mixture
containing 4.3 g. of 3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone, 2.8
g. of anhydrous potassium carbonate and 40 ml. of dry
dimethylformamide was stirred under nitrogen and heated on a steam
bath for thirty minutes. The resulting fine suspension was cooled
to room temperature and to it was added dropwise with stirring 3.7
g. of methyl tosylate. The resulting mixture was then stirred at
room temperature for eighteen hours, at steam bath temperature for
ninety minutes, cooled and then poured onto ice. The separated
solid was collected, washed well with water and dried at 60.degree.
C. and one-third atmosphere for 8 hours. The resulting powder (3.2
g.) was crystallized from 50% aqueous ethanol to yield fine needles
which were washed well with water and dried in vacuo for 3 hours at
100.degree. C. and 10 mm. to yield 2.2 g. of
1-methyl-3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone, m.p.
250.degree.-252.degree. C. In order to prove that the product
obtained here was the N-methyl compound and not the O-methyl
compound the following experiment was conducted: To 300 mg. of the
product dissolved in 10 ml. of glacial acetic acid was added 2 ml.
of 48% hydrogen bromide and the resulting clear solution was heated
on a steam bath for about seventy-five minutes, cooled and the
solvents distilled-off under reduced pressure. The residual yellow
solid was triturated with dilute aqueous ammonium hydroxide
solution, collected by filtration, washed with water and dried at
80.degree. C. and one-third atmosphere for 20 hours to yield 0.30
g. of the starting material, m.p. 252.degree.-254.degree. C. Had
the product been the O-methyl compound, that is,
2-methoxy-3-nitro-5-(4-pyridinyl)pyridine, the foregoing refluxing
with hydrogen bromide in acetic acid would have produced the
demethylated compound namely,
3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone.
In another run following the above-described procedure there was
obtained 11.2 g. of
1-methyl-3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone, m.p.
151.degree.-152.degree. C., using 21.7 g. of
3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone, 13.8 g. of anhydrous
potassium carbonate, 300 ml. of dimethylformamide, 18.6 g. of
methyl tosylate in 50 ml. of dimethylformamide added in one
portion, and recrystallization from aqueous ethanol.
C-5. 1-Ethyl-3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone -- A mixture
containing 21.7 g. of 3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone,
13.8 g. of anhydrous potassium carbonate and 400 ml. of dry
dimethylformamide was stirred at room temperature for 1 hour on a
steam bath for 1 hour and then allowed to cool to room temperature.
To the stirred yellow suspension was added a solution containing 20
g. of ethyl tosylate in 10 ml. of dimethylformamide and the
resulting mixture was stirred at room temperature overnight (about
15 hours) and then on a steam bath for ninety minutes. The mixture
was cooled and filtered. The filtrate was concentrated to near
dryness under reduced pressure and 400 ml. of water was added,. The
yellow solid was collected by filtration, washed with water and
dried at 50.degree. C. in vacuo for 18 hours to yield 5.5 g. of
pale yellow needles, m.p. 124.degree.-126.degree. C. (see below for
recrystallization and identification). The filtrate was stored at
0.degree. C. and the resulting yellow crystalline precipitate was
collected and dried at 100.degree. C. and 10 mm. for four hours to
yield 8.0 g. of the product,
1-ethyl-3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone, m.p.
175.degree.-176.degree. C. A sample of this product was
recrystallized from 95% ethanol to produce the yellow crystalline
1-ethyl compound, m.p. 175.degree.-176.degree. C., whose nuclear
magnetic resonance spectrum (10% in CF.sub.3 COOD) is consistent
with the assigned N-ethyl structure. A portion of the above-noted
pale yellow needles melting at 124.degree.-126.degree. C. was
recrystallized from ethanol-water (3/1, v/v) to yield white
needles, m.p. 126.degree.-127.degree. C., which was identified by
its nuclear magnetic resonance spectrum (10% in CF.sub.3 COOD) as
2-ethoxy-3-nitro-5-(4-pyridinyl)pyridine.
Following the procedure described in Example C-1 but using in place
of 1,2-dihydro-2-oxo-5-(4-pyridinyl)-nicotinic acid a molar
equivalent quantity of the appropriate
1,2-dihydro-2-oxo-5-PY-nicotinic acid, the corresponding
3-nitro-5-PY-2(1H)-pyridinones of Examples C-6 thru C-9 are
obtained.
C-6. 3-Nitro-5-(2-methyl-3-pyridinyl)-2(1H)-pyridinone using
1,2-dihydro-2-oxo-5-(2-methyl-3-pyridinyl)-nicotinic acid.
C-7. 3-Nitro-5-(5-methyl-3-pyridinyl)-2(1H)-pyridinone using
1,2-dihydro-2-oxo-5-(5-methyl-3-pyridinyl)-nicotinic acid.
C-8. 3-Nitro-5-(3-ethyl-4-pyridinyl)-2(1H)-pyridinone using
1,2-dihydro-2-oxo-5-(3-ethyl-4-pyridinyl)-nicotinic acid.
C-9. 3-Nitro-5-(4,6-dimethyl-2-pyridinyl)-2(1H)-pyridinone using
1,2-dihydro-2-oxo-5-(4,6-dimethyl-2-pyridinyl)-nicotinic acid.
Following the procedure described in Example C-5 but using in place
of ethyl tosylate a molar equivalent quantity of the appropriate
lower-alkyl tosylate or other lower-alkylating agents, the
corresponding 1-(lower-alkyl)-3-nitro-5-PY-2(1H)-pyridinones of
Examples C-10, C-11, C-12 and C-13 are obtained.
C-10. 3-Nitro-1-n-propyl-5-(4-pyridinyl)-2(1H)-pyridinone using
3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone and n-propyl tosylate.
C-11. 1-Isobutyl-5-(2-methyl-3-pyridinyl)-3-nitro-2(1H)-pyridinone
using 5-(2-methyl-3-pyridinyl)-3-nitro-2(1H)-pyridinone and
isobutyl tosylate.
C-12. 1-n-Hexyl-3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone using
3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone and n-hexyl tosylate.
C-13. 1-(2-Hydroxyethyl)-3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone
using 3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone and 2-hydroxyethyl
tosylate.
C-14. 3-Nitro-1-n-propyl-5-(4-pyridinyl)-2(1H)-pyridinone -- A
suspension containing 62.5 g. of
3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone, 41.5 g. of anhydrous
potassium carbonate and 1 liter of dimethylformamide was stirred
and heated on a steam bath for thirty minutes. The reaction mixture
was then cooled to about 40.degree. C. and 51.0 g. of n-propyl
iodide was added in one portion and the resulting mixture was
stirred at room temperature for ninety minutes and then at
100.degree. C for 4 hours. The reaction mixture was filtered and
the filtrate was concentrated to about one-third of its volume
under reduced pressure. The resulting mixture was poured into 1
liter of cold water whereupon a red viscous oil separated. The
mixture was extracted with three 150 ml. portions of chloroform and
the combined extracts were washed successively with two 150 ml.
portions of water and two 150 ml. portions of saturated brine and
then dried over anhydrous magnesium sulfate, treated with
decolorizing charcoal and filtered. The filtrate was distilled
under reduced pressure to remove the chloroform, thereby leaving
66.5 g. of dark viscous oil. A 60 g. portion of said dark viscous
oil was dissolved in 200 ml. of glacial acetic acid, 100 ml. of 48%
hydrogen bromide was added, and the solution was stirred on a steam
bath for 6 hours. After distilling off most of the solvents under
reduced pressure, there was added 200 ml. of water and 200 ml of
methylene dichloride and the mixture was made basic (pH of about
10) with 2N potassium hydroxide solution. The layers were separated
and the aqueous layer was extracted with two 100 ml. portions of
methylene dichloride. The combined organic layers were shaken with
brine and dried over anhydrous magnesium sulfate. The methylene
dichloride was distilled off under reduced pressure to leave 35.6
g. of pale yellow, viscous oil which crystallized completely on
standing at room temperature. The crystalline product was
recrystallized from boiling water and dried at 80.degree. C. and
one-third atmosphere for eighteen hours to yield a first crop of
30.2 g. of 3-nitro-1-n-propyl-5-(4-pyridinyl)-2(1H)-pyridinone,
m.p. 139.degree.-140.degree. C. A second crop of 3.8 g. of product,
m.p. 138.degree.-140.degree. C., also was obtained.
D. 3-AMINO-5-(PYRIDINYL)-2-(1H)-PYRIDINONES (From 3-nitro
compounds)
D-1. 3-Amino-5-(4-pyridinyl)-2(1H)-pyridinone -- A mixture
containing 10 g. of 3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone, 200
ml. of dimethylformamide and 1.5 g. of 10% palladium-on-charcoal
was hydrogenated under pressure (50 p.s.i.) at room temperature
until the uptake of hydrogen ceased (about thiry minutes). The
reaction mixture was filtered through infusorial earth and the
filtrate was heated in vacuo to remove the solvent. The residual
material was crystallized from dimethylformamide, washed
successively with ethanol and ether, and dried in a vacuum oven at
80.degree. C. for 8 hours to yield 6 g. of
3-amino-5-(4-pyridinyl)-2(1H)-pyridinone, m.p.
294.degree.-297.degree. C. with decomposition.
The preparations of several acid-addition salts of
3-amino-5-(4-pyridinyl)-2(1H)-pyridinone are given in the following
paragraphs.
Methanesulfonate -- A 20 g. portion of
3-amino-5-(4-pyridinyl)-2(1H)-pyridinone was suspended in 250 ml.
of warm methanol and methanesulfonic acid was added in a fine
stream until the pH of the mixture dropped to about 2 to 3. The
mixture was chilled and the separated orange solid was collected.
The crystalline solid was recrystallized twice from aqueous
methanol to yield, as golden crystals, 14 g. of
3-amino-5-(4-pyridinyl)-2(1H)-pyridinone methanesulfonate, m.p.
280.degree.-282.degree. C. with decomposition, after drying in
vacuo at 80.degree. C.
Sulfate -- To a solution containing 10 g. of
3-amino-5-(4-pyridinyl)-2(1H)-pyridinone in about 250 ml. of
aqueous methanol was added carefully concentrated sulfuric acid
until the pH of the solution became 3. A yellow solid formed and
the mixture was chilled. The separated solid was collected,
recrystallized from water and dried at 80.degree. C. and 0.11 mm.
to yield 16.0 g. of 3-amino-5-(4-pyridinyl)-2(1H)-pyridinone
sulfate, m.p. 287.degree.-288.degree. C. with decomposition.
Phosphate -- A 10 g. portion of
3-amino-5-(4-pyridinyl)-2(1H)-pyridinone was dissolved in
methanol-water and the solution made acidic by adding concentrated
phosphoric acid to a pH of 2 and the mixture was stirred well and
then allowed to stand over the weekend. The mixture was chilled;
the separated solid was collected and washed successively with
ethanol and ether, and then dried in vacuo at 70.degree. C. to
yield 4 g. of 3-amino-5-(4-pyridinyl)-2(1H)-pyridinone phosphate,
m.p. 270.degree.-272.degree. C. with decomposition.
D-2. 3-Amino-5-(3-pyridinyl)-2(1H)-pyridinone -- A mixture
containing 14 g. of 3-nitro-5-(3-pyridinyl)-2(1H)-pyridinone, 300
ml. of dimethylformamide and 1.75 g. of 10% palladium-on-charcoal
was hydrogenated under pressure (50 p.s.i.) at room temperature for
2 hours and then filtered. The solvent was distilled off in vacuo
and the residue was slurried with isopropyl alcohol. The solid was
collected by filtration and washed with ether and then dried. The
solid was dissolved in dilute aqueous hydrochloric acid; the
solution was treated with decolorizing charcoal and filtered; and,
the filtrate was evaporated in vacuo. The residue was slurried with
isopropyl alcohol; the solid collected by filtration, washed with
ether and dried at 80.degree. C. in vacuo to produce 11 g. of
3-amino-5-(3-pyridinyl)-2(1H)-pyridinone as its dihydrochloride,
m.p. 280.degree.-290.degree. C. with decomposition.
D-3. 3-Amino-5-(2-pyridinyl)-2(1H)-pyridinone -- A mixture
containing 10 g. of 3-nitro-5-(2-pyridinyl)-2(1H)-pyridinone, 150
ml. of dimethylformamide and 1.5 g. of 10% palladium-on-charcoal
was hydrogenated under pressure (50 p.s.i.) at room temperature for
1 hour and filtered. The filter cake was washed with
dimethylformamide. The combined filtrate and washings were
evaporated in vacuo and the residual material was taken up in 6N
aqueous hydrochloric acid. The acidic solution was evaporated in
vacuo and the residue was recrystallized from dimethylformamide,
washed successively with isopropyl alcohol and ether, and dried at
80.degree. C. in vacuo to yield 2 g. of
3-amino-5-(2-pyridinyl)-2(1H)-pyridinone as its monohydrochloride,
m.p. 259.degree.-262.degree. C. with decomposition.
D-4. 3-Amino-1-methyl-5-(4-pyridinyl)-2(1H)-pyridinone -- A mixture
containing 10.7 g. of
1-methyl-3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone and 200 ml. of
dimethylformamide was warmed to dissolve the nitro-pyridinone and
the solution was filtered through infusorial earth. The filtrate
was charged into a 500 ml. Parr bottle with 1.2 g. of 10%
palladium-on-charcoal catalyst and the mixture was shaken under 40
p.s.i. of hydrogen at room temperature for three hours, after which
time no further hydrogen was taken up. The reaction mixture was
filtered and the filtrate was concentrated to dryness under reduced
pressure (0.1 mm.) on a water bath at 40.degree. C. leaving 10.1 g.
of brown crystalline solid. The solid was recrystallized three
times from benzene-ethanol, the third time using decolorizing
charcoal, to yield 4.5 g. of
3-amino-1-methyl-5-(4-pyridinyl)-2(1H)-pyridinone, m.p.
175.degree.-176.degree. C. after drying at room temperature in
vacuo for 20 hours.
D-5. 3-Amino-1-ethyl-5-(4-pyridinyl)-2(1H)-pyridinone -- A solution
containing 8.3 g. of
1-ethyl-3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone in 200 ml. of
ethyl acetate and 50 ml. of 95% ethanol was charged into a 500 ml.
Parr bottle with 1.8 g. of 10% palladium-on-charcoal and the
mixture was shaken under 42 p.s.i. of hydrogen at room temperature
for fifty minutes after which time no further hydrogen was taken
up. The catalyst was filtered off and the solution was evaporated
in vacuo to leave 7.5 g. of white crystalline solid. The solid was
recrystallized from benzene to produce, as white needles, 5.8 g. of
3-amino-1-ethyl-5-(4-pyridinyl)-2(1H)-pyridinone, m.p.
181.degree.-182.degree. C. after drying at room temperature in
vacuo for 50 hours and at 55.degree. C. and 0.001 mm. for 5
hours.
Following the procedure described in Example D-4 but using in place
of 1-methyl-3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone a molar
equivalent quantity of the appropriate
1-R-3-nitro-5-PY-2(1H)-pyridinone, the
1-R-3-amino-5-PY-2(1H)-pyridinones of Examples D-6 thru D-13 are
obtained.
D-6. 3-Amino-1-n-propyl-5-(4-pyridinyl)-2(1H)-pyridinone using
1-n-propyl-3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone.
D-7. 3-Amino-1-isobutyl-5-(4-pyridinyl)-2(1H)-pyridinone using
1-isobutyl-3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone.
D-8. 3-Amino-1-n-hexyl-5-(4-pyridinyl)-2(1H)-pyridinone using
1-n-hexyl-3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone.
D-9. 3-Amino-5-(2-methyl-3-pyridinyl)-2(1H)-pyridinone using
3-nitro-5-(2-methyl-3-pyridinyl)-2(1H)-pyridinone.
D-10. 3-Amino-5-(5-methyl-3-pyridinyl)-2(1H)-pyridinone using
3-nitro-5-(5-methyl-3-pyridinyl)-2(1H)-pyridinone.
D-11. 3-Amino-5-(3-ethyl-4-pyridinyl)-2(1H)-pyridinone using
3-nitro-5-(3-ethyl-4-pyridinyl)-2(1H)-pyridinone.
D-12. 3-Amino-5-(4,6-dimethyl-2-pyridinyl)-2(1H)-pyridinone using
3-nitro-5-(4,6-dimethyl-2-pyridinyl)-2(1H)-pyridinone.
D-13. 3-Amino-1-(2-hydroxyethyl)-5-(4-pyridinyl)-2(1H)-pyridinone
using
1-(2-hydroxyethyl)-3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone.
D-14. 3-Amino-1-n-propyl-5-(4-pyridinyl)-2(1H)-pyridinone -- A
solution containing 15.1 g. of
3-nitro-1-n-propyl-5-(4-pyridinyl)-2(1H)-pyridinone in 400 ml. of
dry dimethylformamide was charged into an 800 ml. Parr bottle with
1.5 teaspoons of Raney nickel and the mixture was shaken under 650
p.s.i. of hydrogen at room temperature for 4 hours, during which
time the reaction temperature was no more than 50.degree. C. The
catalyst was filtered off; the filtrate was treated with
decolorizing charcoal and filtered; and, the solvent was distilled
off under reduced pressure to leave 12.7 g. of crystalline solid.
The solid was recrystallized from methanol to yield 7.2 g. of
crystalline 3-amino-1-n-propyl-5-(4-pyridinyl)-2(1H)-pyridinone,
m.p. 171.degree.-173.degree. C. after drying at 70.degree. C. and
0.001 mm. for 6 hours.
E. 1,2-DIHYDRO-2-OXO-5-(PYRIDINYL)NICOTINAMIDES
E-1. 1,2-Dihydro-2-oxo-5-(4-pyridinyl)nicotinamide (optionally
named 1,6-dihydro-6-oxo[3,4'-bipyridin]-5-carboxamide) -- A mixture
containing 10 g. of
1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile and 100 ml. of 90%
sulfuric acid was heated on a steam bath for one hour and then
poured into ice. The acidic solution was neutralized with 35%
aqueous sodium hydroxide solution and then made basic with 10%
potassium bicarbonate solution. The separated product was
collected, washed with water, dried, recrystallized from
dimethylformamide, washed successively with ethanol and ethyl
ether, and dried in vacuo at 80.degree. C. to yield 8.5 g. of
1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinamide, m.p. >300.degree.
C.
In another run using 68 g. of
1,2-dihydro-2-oxo-4-(4-pyridinyl)nicotinonitrile, 700 ml. of 90%
sulfuric acid, a heating period of two hours on a steam bath,
isolation as above, recrystallization from dimethylformamide and
washing with methanol and ether followed by drying, there was
obtained a quantative yield, 80 g. of the product,
1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinamide, m.p. 300.degree.
C.
E-2. 1,2-Dihydro-5-(4-pyridinyl)nicotinamide -- A reaction mixture
containing 17.6 g. of
.alpha.-(4-pyridinyl)-.beta.-dimethylaminoacrolein, 10.0 g. of
malonamide, 10.8 g. of sodium methoxide and 200 ml. of methanol was
refluxed for thirty minutes and allowed to cool. The separated
product was collected and dried to yield "A". The mother liquor was
concentrated in vacuo to remove the solvent and the residual
material was diluted with water. The mixture was neutralized with
acetic acid and the solid was collected, washed with water and
dried to yield "B". "A" was dissolved in water and the solution was
neutralized with acetic acid and the mixture cooled. The separated
solid was collected, washed with water and dried. "A" and "B" were
combined and recrystallized from 400 ml. of dimethylformamide to
yield 13 g. of 1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinamide, m.p.
>300.degree. C. The product obtained by this procedure was
identical with the compound obtained in the immediately preceding
Example E-1.
Following the procedure described in Example E-1 but using in place
of 1,2-dihydro-2-oxo-5-(4-pyridinyl)-nicotinonitrile a molar
equivalent quantity of the appropriate
1,2-dihydro-2-oxo-5-PY-nicotinonitrile, the
1,2-dihydro-2-oxo-5-PY-nicotinamides of Examples E-3 thru E-8 are
obtained.
E-3. 1,2-Dihydro-2-oxo-5-(3-pyridinyl)nicotinamide using
1,2-dihydro-2-oxo-5-(3-pyridinyl)nicotinonitrile.
E-4. 1,2-Dihydro-2-oxo-5-(2-pyridinyl)nicotinamide using
1,2-dihydro-2-oxo-5-(2-pyridinyl)nicotinonitrile.
E-5. 1,2-Dihydro-2-oxo-5-(2-methyl-3-pyridinyl)-nicotinamide using
1,2-dihydro-2-oxo-5-(2-methyl-3-pyridinyl)-nicotinonitrile.
E-6. 1,2-Dihydro-2-oxo-5-(5-methyl-3-pyridinyl)-nicotinamide using
1,2-dihydro-2-oxo-5-(5-methyl-3-pyridinyl)-nicotinonitrile.
E-7. 1,2-Dihydro-2-oxo-5-(3-ethyl-4-pyridinyl)-nicotinamide using
1,2-dihydro-2-oxo-5-(3-ethyl-4-pyridinyl)-nicotinonitrile.
E-8. 1,2-Dihydro-2-oxo-5-(4,6-dimethyl-2-pyridinyl)-nicotinamide
using
1,2-dihydro-2-oxo-5-(4,6-dimethyl-2-pyridinyl)-nicotinonitrile.
The products of E-3 thru E-8 also are produced by following the
procedure described in Example E-2 using in place of
.alpha.-(4-pyridinyl)-.beta.-dimethylacrolein a molar equivalent
quantity of the appropriate .alpha.-PY-.beta.-dimethylacrolein,
e.g., 1,2-dihydro-2-oxo-5-(3-pyridinyl)nicotinamide using
.alpha.-(3-pyridinyl)-.beta.-dimethylaminoacrolein, and the
like.
F. 3-AMINO-5-(PYRIDINYL)-2(1H)-PYRIDINONES (From 3-CONH.sub.2
compounds)
F-1. 3-Amino-5-(4-pyridinyl)-2(1H)-pyridinone -- To a solution
containing 90 g. of sodium hydroxide in 1300 ml. of water kept at
0.degree. C. was added dropwise with stirring 23 ml. of bromine. To
the reaction mixture was then added 80 g. of
1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinamide and the resulting
reaction mixture was heated on a steam bath for three hours. The
reaction mixture was cooled to room temperature, acidified slowly
with 6N hydrochloric acid and the resulting acidic mixture was
stirred for an additional thirty minutes. The acidic mixture was
neutralized with 10% aqueous potassium bicarbonate solution and the
mixture cooled. The precipitate was collected, washed with water
and dried. The solid product was recrystallized from
dimethylformamide, washed successively with methanol and ethyl
ether and dried in vacuo at 80.degree. C. to yield 35 g. of
3-amino-5-(4-pyridinyl)-2(1H)-pyridinone, m.p.
295.degree.-297.degree. C. with decomposition. Another 7 g. of the
product was obtained by diluting the mother liquor with ethyl
ether.
Following the procedure described in Example F-1 but using in place
of 1,2-dihydro-2-oxo-5-(4-pyridinyl)-nicotinamide a molar
equivalent quantity of the appropriate
1,2-dihydro-2-oxo-5-PY-nicotinamide, the
3-amino-5-PY-2(1H)-pyridinones of Examples F-2 thru F-7 are
obtained.
F-2. 3-Amino-5-(3-pyridinyl)-2(1H)-pyridinone using
1,2-dihydro-2-oxo-5-(3-pyridinyl)nicotinamide.
F-3. 3-Amino-5-(2-pyridinyl)-2(1H)-pyridinone using
1,2-dihydro-2-oxo-5-(2-pyridinyl)nicotinamide.
F-4. 3-Amino-5-(2-methyl-3-pyridinyl)-2(1H)-pyridinone using
1,2-dihydro-2-oxo-5-(2-methyl-3-pyridinyl)-nicotinamide.
F-5. 3-Amino-5-(5-methyl-3-pyridinyl)-2(1H)-pyridinone using
1,2-dihydro-2-oxo-5-(5-methyl-3-pyridinyl)-nicotinamide.
F-6. 3-Amino-5-(3-ethyl-4-pyridinyl)-2(1H)-pyridinone using
1,2-dihydro-2-oxo-5-(3-ethyl-4-pyridinyl)-nicotinamide.
F-7. 3-Amino-5-(4,6-dimethyl-2-pyridinyl)-2(1H)-pyridinone using
1,2-dihydro-2-oxo-5-(4,6-dimethyl-2-pyridinyl)-nicotinamide.
G. 1,2-DIHYDRO-3-(ACYLAMIDO)-5-(PYRIDINYL)-2(1H)-PYRIDINONES
G-1. N-[1,2-Dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]acetamide --
A mixture containing 9.4 g. of
3-amino-5-(4-pyridinyl)-2(1H)-pyridinone, 5.6 g. of acetic
anhydride and 120 ml. of pyridine was heated on a steam bath for
one hour and then allowed to cool. The separated product was
collected, washed with ether and dried, and recrystallized twice
from dimethylformamide to yield 8 g. of
N-[1,2-dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]acetamide, m.p.
>300.degree. C.
G-2. Methyl
N-[1,2-dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]carbamate -- A
mixture containing 10 g. of
3-amino-5-(4-pyridinyl)-2(1H)-pyridinone, 100 ml. of
dimethylformamide and 24 g. of 1,1'-carbonyldiimidazole was stirred
at room temperature for 2 hours and the solvent then distilled off
in vacuo. Cold water was added to the residue and the mixture was
stirred until the evolution of carbon dioxide stopped. The solid
was collected, washed with water and dried. The solid was next
slurried with acetone, collected and dried. The solid was dissolved
in 200 ml. of dimethylformamide, the solution treated with
decolorizing charcoal and the mixture filtered. The filtrate was
heated in vacuo to remove the dimethylformamide. The remaining
material, which consisted primarily of
N-[1,2-dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]-imidazole-1-carboxamide,
was heated with methanol whereupon a reaction ensued. The reaction
mixture was allowed to cool and the separated product was collected
and dried to yield 3.5 g. of methyl
N-[1,2-dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]carbamate, m.p.
>300.degree. C.
Following the procedure described in Example G-1 but using in place
of acetic anhydride a molar equivalent quantity of the appropriate
acylating agent, the compounds of Examples G-3 thru G-5 are
obtained.
G-3. N-[1,2-Dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]propionamide
using propionic anhydride.
G-4. N-[1,2-Dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]isobutyramide
using isobutyric anhydride.
G-5. N-[1,2-Dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]caproamide
using caproic anhydride.
Following the procedure described in Example G-2 but first using in
place of 3-amino-5-(4-pyridinyl)-2(1H)-pyridinone a corresponding
molar equivalent quantity of the appropriate
3-amino-5-PY-2(1H)-pyridinone to produce the corresponding
N-(1,2-dihydro-2-oxo-5-PY-3-pyridinyl)-imidazole-1-carboxamide and
then reacting said imidazole-1-carboxamide with the appropriate
alkanol in place of methanol, there are obtained the corresponding
lower-alkyl N-(1,2-dihydro-2-oxo-5-PY-3-pyridinyl)carbamates of
Examples G-6 thru G-8.
G-6. Ethyl
N-[1,2-dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]carbamate first
using 3-amino-5-(4-pyridinyl)-2(1H)-pyridinone and then using
ethanol.
G-7. n-Hexyl
N-[1,2-dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]carbamate using
3-amino-5-(4-pyridinyl)-2(1H)-pyridinone and then reacting the
resulting
N-[1,2-dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]-imidazole-1-carboxamide
with n-hexanol.
G-8. Isobutyl
N-[1,2-dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]carbamate first
using 3-amino-5-(4-pyridinyl)-2(1H)-pyridinone and then reacting
the resulting
N-[1,2-dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]-1-imidazole-1-carboxamid
e with isobutyl alcohol.
G-9. N-[1,2-Dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]formamide
(also named N-(1,6-dihydro-6-oxo-[3,4'-bipyridine]-5-yl)formamide)
-- A reaction mixture containing 28 g. of
3-amino-5-(4-pyridinyl)-2(1H)-pyridinone and 200 ml. of 97% formic
acid was heated on a steam bath for 3 hours, cooled and the excess
formic acid distilled-off under reduced pressure. The residue was
dissolved in water and the aqueous solution was made alkaline with
ammonium hydroxide. The precipitated product was collected, washed
with water, dried, recrystallized from dimethylformamide, washed
with ether and dried to yield 26 g. of
N-[1,2-dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]formamide, m.p.
299.degree.-300.degree. C. with decomposition.
H. 3-HALO-5-(PYRIDINYL)-2(1H)-PYRIDINONES
H-1. 3-Bromo-5-(4-pyridinyl)-2(1H)-pyridinone (also named
5-bromo-[3,4'-bipyridin]-6(1H)-one) -- A mixture containing 51.6 g.
of 5-(4-pyridinyl)-2(1H)-pyridinone and 600 ml. of acetic acid was
heated to about 60.degree. C. to effect complete solution. The heat
was removed and 52.8 g. of bromine was added dropwise over a period
of about 20 minutes whereupon a solid separated during the
addition. The mixture was stirred at room temperature for about 30
minutes, diluted with ether and the mixture then chilled in ice.
The solid was collected, washed with ether, dried, slurried with
water and neutralized with 10% potassium bicarbonate solution. The
solid was collected, washed with water and dried. The solid was
then dissolved in dilute hydrochloric acid and isopropyl alcohol
was added to the solution to precipitate the hydrochloride salt
which was recrystallized from water and dried to yield 55 g. of
3-bromo-5-(4-pyridinyl)-2(1H)-pyridinone as its hydrochloride, m.p.
>300.degree. C.
H-2. 3-Chloro-5-(4-pyridinyl)-2(1H)-pyridinone (also named
5-chloro-[3,4'-bipyridin]-6(1H)-one) -- A mixture containing 17 g.
of 5-(4-pyridinyl)-2(1H)-pyridinone and 200 ml. of acetic acid
heated on a steam bath was treated by bubbling chlorine into it for
4 hours. After allowing the reaction mixture to cool to room
temperature, the solid was collected, washed with ether and dried.
The solid was dissolved in water and the aqueous solution was
neutralized with 2N aqueous potassium hydroxide solution and the
mixture cooled. The separated solid was collected, washed with
water, dried, and recrystallized from ethanol to yield 6.5 g. of
3-chloro-5-(4-pyridinyl)-2(1H)-pyridinone, m.p.
295.degree.-297.degree. C.
H-3. 3-Chloro-5-(3-pyridinyl)-2(1H)-pyridinone is obtained
following the procedure described in Example H-2 but using a molar
equivalent quantity of 5-(3-pyridinyl)-2(1H)-4-pyridinone in place
of 5-(4-pyridinyl)-2(1H)-pyridinone.
H-4. 3-Chloro-5-(3-ethyl-4-pyridinyl)-2(1H)-pyridinone is obtained
following the procedure described in Example H-2 using a molar
equivalent quantity of 5-(3-ethyl-4-pyridinyl)-2(1H)-pyridinone in
place of 5-(4-pyridinyl)-2(1H)-pyridinone.
H-5. 3-Bromo-5-(5-methyl-3-pyridinyl)-2(1H)-pyridinone is obtained
following the procedure described in Example H-1 using
5-(5-methyl-3-pyridinyl)-2(1H)-pyridinone in place of
5-(4-pyridinyl)-2(1H)-pyridinone.
I. 3-(LOWER-ALKYLAMINO)- AND
3-[DI-(LOWER-ALKYL)-AMINO]-5-(PYRIDINYL)-2(1H)-PYRIDINONES
I-1. 3-Methylamino-5-(4-pyridinyl)-2(1H)-pyridinone (also named
5-methylamino-[3,4'-bipyridin]-6-(1H)one) -- A mixture containing
55 g. of 3-bromo-5-(4-pyridinyl)-2(1H)-pyridinone, 200 ml. of 40%
aqueous monomethylamine and 500 ml. of water was autoclaved at
140.degree. C. for 120 hours. After allowing the reaction mixture
to cool to room temperature, the solid was collected, washed with
water, dried, recrystallized from dimethylformamide, washed
successively with methanol and ether, and dried to yield 10 g. of
3-methylamino-5-(4-pyridinyl)-2(1H)-pyridinone, m.p.
296.degree.-299.degree. C. with decomposition. Another 8 g. of
product was obtained by stripping under reduced pressure the
aqueous filtrate from the reaction mixture, slurrying the remaining
residue with a small amount of water, collecting the solid and
recrystallizing it from dimethylformamide.
I-2. 3-Dimethylamino-5-(4-pyridinyl)-2(1H)-pyridinone (also named
5-(dimethylamino)-[3,4-bipyridin]-6-(1H)-one) - A mixture contaning
36 g. of 3-amino-5-(4-pyridinyl)-2(1H)-pyridinone, 40 g. of 30%
aqueous formaldehyde solution and 400 ml. of formic acid was
refluxed for 21/2 hours and cooled. The reaction mixture was heated
in vacuo to remove the excess formaldehyde and formic acid and the
remaining material was neutralized with 10% potassium bicarbonate
solution and allowed to stand at room temperature over the weekend.
The aqueous mixture was extracted with three 150 ml. portions of
methylene dichloride and the combined extracts were dried over
anhydrous magnesium sulfate and treated with decolorizing charcoal,
filtered and the filtrate heated in vacuo to remove the methylene
dichloride. The residue was recrystallized twice from acetonitrile,
washed with ether and dried in a vacuum oven at 80.degree. C. to
yield 11.5 g. of 3-dimethylamino-5-(4-pyridinyl)-2(1H)-pyridinone,
m.p. 190.degree.- 194.degree. C.
Following the procedure described in Example I-1 but in place of
3-bromo-5-(4-pyridinyl)-2(1H)-pyridinone and/or monomethylamine
respective molar equivalent quantities of the appropriate
3-halo-5-(pyridinyl)-2(1H)-pyridinone and/or lower-alkylamine or
di-(lower-alkyl)amine, the compounds of Examples I-3 thru I-7 are
obtained: I-3. 3-Ethylamino-5-(3-pyridinyl)-2(1H)-pyridinone using
3-chloro-5-(3-pyridinyl)-2(1H)-pyridinone and monoethylamine.
I-4. 3-Diethylamino-5-(4-pyridinyl)-2(1H)-pyridinone using
3-bromo-5-(4-pyridinyl)-2(1H)-pyridinone and diethylamine.
I-5. 3-n-Propylamino-5-(3-ethyl-4-pyridinyl)-2(1H)-pyridinone using
3-chloro-5-(3-ethyl-4-pyridinyl)-2(1H)-pyridinone and
n-propylamine.
I-6. 3-(Diisopropylamino)-5-(5-methyl-3-pyridinyl)-2(1H)-pyridinone
using 3-bromo-5-(5-methyl-3-pyridinyl)-2(1H)-pyridinone and
diisopropylamine.
I-7. 3-n-Hexylamino-5-(4-pyridinyl)-2(1H)-pyridinone using
3-bromo-5-(4-pyridinyl)-2(1H)-pyridinone and mono-n-hexylamine.
J. DI-(LOWER-ALKYL)
N-[1,2-DIHYDRO-2-OXO-5-(PYRIDINYL)-3-PYRIDINYL]AMINOMETHYLENEMALONATE
J-1. Diethyl
N-[1,2-dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]aminomethylenemalonate
(also named diethyl
[1,6-dihydro-6-oxo-(3,4'-bipyridin)-5-ylaminomethylene]propanedioate)
- A mixture containing 9.4 g. of
3-amino-5-(4-pyridinyl)-2(1H)-pyridinone, 10.8 g. of diethyl
ethoxymethylenemalonate and 100 ml. of ethanol was refluxed with
stirring on a steam bath for 61/2 hours. The reaction mixture was
filtered through infusorial earth and the filtrate was distilled in
vacuo to remove the solvent. The solid residue was recrystallized
once from ethanol and then once from methanol using decolorizing
charcoal, washed successively with isopropyl alcohol and ether, and
then dried to yield 22 g. of diethyl
N-[1,2-dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]aminomethylenemalonate,
m.p. 218.degree.-222.degree. C.
Following the procedure described in Example J-1 but using in place
of diethyl ethoxymethylenemalonate a molar equivalent quantity of
the appropriate di-(lower-alkyl) (lower-alkoxy)methylenemalonate
and/or using in place of 3-amino-5-(4-pyridinyl)-2(1H)-pyridinone a
molar equivalent quantity of the appropriate
3-amino-5-(pyridinyl)-2(1H)-pyridinone, the compounds of Examples
J-2 thru J-6 are obtained:
J-2. Dimethyl
N-[1,2-dihydro-2-oxo-5-(2-methyl-4-pyridinyl)-3-pyridinyl]aminomethylenema
lonate using dimethyl methoxymethylenemalonate and
3-amino-5-(2-methyl-4-pyridinyl)-2(1H)-pyridinone.
J-3. Diethyl
N-[1,2-dihydro-2-oxo-5-(3-pyridinyl)-3-pyridinyl]aminomethylenemalonate
using diethyl ethoxymethylenemalonate and
3-amino-5-(3-pyridinyl)-2(1H)-pyridinone.
J-4. Diisopropyl
N-[1,2-dihydro-2-oxo-5-(5-methyl-3-pyridinyl)-3-pyridinyl]aminomethylenema
lonate using diisopropyl isopropoxymethylenemalonate and
3-amino-5-(5-methyl-3-pyridinyl)-2(1H)-pyridinone.
J-5. Di-n-butyl
N-[1,2-dihydro-2-oxo-5-(2-methyl-4-pyridinyl)-3-pyridinyl]aminomethylenema
lonate using di-n-butyl n-butoxymethylenemalonate and
3-amino-5-(2-methyl-4-pyridinyl)-2(1H)-pyridinone.
J-6. Di-n-hexyl
N-[1,2-dihydro-2-oxo-5-(2,6-dimethyl-4-pyridinyl)-3-pyridinyl]aminomethyle
nemalonate using di-n-hexyl n-hexoxymethylenemalonate and
3-amino-5-(2,6-dimethyl-4-pyridinyl)-2(1H)-pyridinone.
The usefulness of the compounds of formula I where Q is amino
(preferred), lower-alkylamino, di-(lower-alkyl)-amino, NHAc,
hydrogen or cyano and the compounds of formula V as cardiotonic
agents is demonstrated by their effectiveness in standard
pharmacological test procedures, for example, in causing a
significant increase in the contractile force of the isolated cat
atria and papillary muscle and in causing a significant increase in
the cardiac contractile force in the anesthetized dog with low or
minimal changes in heart rate and blood pressure. These test
procedures are described in the following paragraphs.
Isolated Cat Atria and Papillary Muscle Procedure -- Cats of both
sexes, weighing 1.5 to 3.5 kg. are each anesthetized with 30
mg./kg. i.p. of sodium pentobarbital and exsanguinated. The chest
of each cat is opened, the heart excised, rinsed with saline, and
the two atria and one or more small, thin papillary muscles from
the right ventricle are dissected. The tissues are then transferred
to a Petri dish filled with cold modified Tyrode's solution and
bubbled with O.sub.2. A silver wire is attached to each of two
opposite ends of the tissue and one of the wires is hooked to a
glass electrode. The preparation is then immediately mounted in a
40 or 50 ml. organ bath filled with modified Tyrode's solution at
37.degree. C. The second wire is attached to a force-displacement
transducer and the tension is adjusted to obtain a maximum
contractile force (papillary muscle 1.5.+-.0.5 g., left atria
3.0.+-.0.6 g. right atria 4.5.+-.0.8 g.). The transducer is
connected to a Grass polygraph and the force and rate of
contraction is recorded continuously. The right atrium is beating
spontaneously due to the presence of the sino-atrial node, while
the left atrium and the papillary muscle are stimulated
electrically at a rate of 2 beats/sec. by a suprathreshold
rectangular pulse of 0.5 millisecond duration.
The modified Tyrode's solution bathing the preparation is of the
following composition (in millimoles): NaCl 136.87, KCl 5.36,
NaH.sub.2 PO.sub.4 0.41. CaCl.sub.2 1.8, MgCl.sub.2 . 6H.sub.2 O
1.05, NaHCO.sub.3 11.9, glucose 5.55 and EDTA 0.04. The solution is
equilibrated with a gas mixture consisting of 95% O.sub.2 and 5%
CO.sub.2 and the pH is adjusted to 7.4 with dilute solution of
sodium bicarbonate.
The preparation is left to equilibrate for one hour before any
compound is administered, and the bathing fluid is changed 3 to 4
times during the equilibration time. The compound dissolved in a
vehicle (e.g., Tyrode's solution or aqueous solution of
acid-addition salt of compound tested) or the vehicle alone is
added to the tissue bath and the full response is recorded. The
tissues are washed between doses until pre-drug control values of
rate and force of contraction are obtained. Four to six doses are
given to the same preparation over a period of 4 to 6 hours.
When tested by the above-described Isolated Cat Atria and Papillary
Muscle Procedure, the compounds of formula I where Q is amino,
NHAc, lower-alkylamino, di-(lower-alkyl)amino, NHAc, hydrogen or
cyano and the compounds of formula V, when tested at doses of 3 to
100 .mu.g./ml., were found to cause significant increase, that is,
greater than 25%, in papillary muscle force and a significant
increase, that is, greater than 25%, in right atrial force, while
causing only a low percentage increase (about one-third or less
than the percentage increase in right atrial or papillary muscle
force) in right atrial rate.
Anesthetized Dog Procedure -- Mongrel dogs of both sexes weighing
9-15 kg. are used in this procedure. The dogs are each anesthetized
with 30 mg./kg. i.v. sodium pentobarbital. Supplemental doses of
pentobarbital are administered whenever necessary. An
intra-tracheal cannula is inserted and ventilation is carried out
by means of a Harvard constant-volumne, positive pressure pump
using room air. The right femoral artery is cannulated and the
cannula is attached to a Statham P23A pressure transducer for the
measurement of arterial blood pressure. The right femoral vein is
cannulated and used for intravenous administration of compounds to
be tested. Pin electrodes are attached to the right forelimb, right
hindlimb and left hindlimb, and lead II electrocardiogram is
monitored.
A ventro-dorsal incision at the third inter-costal space is made,
the heart is exposed and a Walton-Brodie strain guage is sutured to
the wall of the right ventricle for the measurement of cardiac
contractile force, that is, cardiac contractility. Aortic and
coronary blood flow are measured with a pulsed field
electromagnetic flow probe (Carolina Medical Electronics) inserted
around the blood vessel in question. Aortic blood flow is used as
an approximate index of cardiac output and total peripheral
resistence is calculated from aortic flow and mean arterial
pressure. All the above parameters measured are recorded
simultaneously on a multi-channel Grass polygraph.
A given compound is infused into the femoral vein at a rate of from
0.03 to 0.10 mg./kg./minute until a maximum inotropic effect is
obtained. The infusion of the compound is then continued for ten
more minutes to maintain an equilibrium at this maximal inotropic
effect. At the end of the equilibrium time the infusion is stopped
and the rate of decline in cardiac contractile force is observed.
Alternatively, the compound is administered intravenously as a
single bolus injection of 0.30 to 30 mg./kg.
When tested by the above-described Anesthetized Dog Procedure, the
compounds of formula I where Q is amino (preferred),
lower-alkylamino, di-(lower-alkyl)amino, NHAc, hydrogen or cyano
and the compounds of formula V, when administered intravenously at
a rate of about 0.03 to 0.10 mg./kg./min. or as a single bolus
injection of 0.30 to 30 mg./kg. caused a significant increase, that
is, greater than 25%, in cardiac contractile force or cardiac
contractility with only low or minimal changes (less than 25%) in
heart rate and blood pressure.
The actual determination of the numerical cardiotonic data
definitive for a particular compound of the invention is readily
obtained according to the above-described standard test procedures
by technicians versed in pharmacological test procedures, without
any need for any extensive experimentation.
Preferred embodiments are subjected to further standard test
procedures. For example, 3-amino-5-(4-pyridinyl)-2(1H)-pyridinone,
a particularly preferred embodiment, when tested orally in the
unanesthetized dog at a dose of 1.9, 3.8, 7.5 or 10 mg./kg. was
found to cause, respectively, a 39, 44, 47 or 98% increase in
cardiac contractile force with a duration of action of more than
three hours; no significant changes in blood pressure were observed
with these doses and a significant increase in heart rate was
observed only at the highest dose of 10 mg./kg. p.o.
The present invention includes within its scope a cardiotonic
composition for increasing cardiac contractility, said composition
comprising a pharmaceutically-acceptable carrier and, as the active
component thereof, a cardiotonic 1-R-3-Q-5-PY-2(1H)-pyridinone of
formula I where Q is amino (preferred), lower-alkylamino,
di-(lower-alkyl)amino, NHAc, hydrogen or cyano, or a cardiotonic
di-(lower-alkyl)
N-[1,2-dihydro-2-oxo-5-(pyridinyl)-3-pyridinyl]aminomethylenemalonate
of formula V, or pharmaceutically-acceptable acid-addition salt
thereof. The invention also includes within its scope the method
for increasing cardiac contractility in a patient requiring such
treatment which comprises administering to such patient an
effective amount of said 1-R-3-Q-5-PY-2(1H)-pyridinone of formula I
where Q is amino (preferred), lower-alkylamino,
di-(lower-alkyl)amino, NHAc, hydrogen or cyano, or a cardiotonic
di-(lower-alkyl)
N-[1,2-dihydro-2-oxo-5-(pyridinyl)-3-pyridinyl]aminomethylenemalonate
of formula V, or pharmaceutically-acceptable acid-addition salt
thereof. In clinical practice the said compounds of formula I or V
will normally be administered orally or parenterally in a wide
variety of dosage forms.
Solid compositions for oral administration include compressed
tablets, pills, powders and granules. In such solid compositions,
at least one of the active compounds is admixed with at least one
inert diluent such as starch, calcium carbonate, sucrose or
lactose. These compositions may also contain additional substances
other than inert diluents, e.g., lubricating agents, such as
magnesium stearate talc and the like.
Liquid compositions for oral administration include
pharmaceutically-acceptable emulsions, solutions, suspensions,
syrups and elixirs containing inert diluents commonly used in the
art, such as water and liquid paraffin. Besides inert diluents such
compositions may also contain adjuvants, such as wetting and
suspending agents, and sweetening, flavouring, perfuming and
preserving agents. According to the invention, the compounds for
oral administration also include capsules of absorbable material,
such as gelatin, containing said active component with or without
the addition of diluents or excipients.
Preparations according to the invention for parenteral
administration include sterile aqueous, aqueous-organic, and
organic solutions, suspensions and emulsions. Examples of organic
solvents or suspending media are propylene glycol, polyethylene
glycol, vegetable oils such as olive oil and injectable organic
esters such as ethyl oleate. These compositions may also contain
adjuvants such as stabilising, preserving, wetting, emulsifying and
dispersing agents.
They may be sterilized, for example by filtration through a
bacteria-retaining filter, by incorporation of sterilising agents
in the compositions, by irradiation or by heating. They may also be
manufactured in the form of sterile solid compositions which can be
dissolved in sterile water or some other sterile injectable medium
immediately before use.
The percentage of active component in the said composition and
method for increasing cardiac contractility may be varied so that a
suitable dosage is obtained. The dosage administered to a
particular patient is variable, depending upon the clinician's
judgement using as the criteria: the route of administration, the
duration of treatment, the size and condition of the patient, the
potency of the active component and the patient's response thereto.
An effective dosage amount of active component can thus only be
determined by the clinician considering all criteria and utilizing
his best judgement on the patient's behalf.
* * * * *